Hypoglycemic compositions and methods for 1-phenylsulfonyl-2-imino-imidazolidines and hexahydropyridines

ABSTRACT

1-Phenylsulfonyl-2-imino-imidazolidines and hexahydropyrimidines, substituted at the heterocyclic ring and substituted or unsubstituted at the phenylring are prepared; these compounds and their pharmaceutically acceptable acid addition salts have hypoglycemic activity; pharmaceutical compositions comprising said compounds and methods of producing hypoglycemic effects in mammals are provided; an illustrative embodiment is 1-sulfanilyl-2-imino-3-butyl-imidazolidine.

United States Patent Dietrich 1 Sept. 26, 1972 [54] HYPOGLYCEMIC COMPOSITIONS [56] References Cited AND METHODS FOR 1- UNITED STATE P T N PHENYLSULFONYLJ-IMINO' 3 507 95s 4/1970 2' S A E TS 424/229 [MIDAZOLIDINES AND immermann BOettl'lel' et ai. [72] inventor: llenriDietrich, Arlesheim, Switzer- Primary Examiner-Jerome D. Goldberg land Attorney--Karl F. Jorda and Bruce M. Collins [73] Assignee: Cibg-Geigy Corporation [57] ABSTRACT [22] Filed: 0 l-Phenylsulfonyl-2-imino-imidazolidines and -hex- [2]] App]. 12,483 ahydropyrimidines, substituted at the heterocyclic ring and substituted or unsubstituted at the phenylring are Related US. Application Data prepared; these compounds and their pharmaceutically acceptable acid addition salts have hypoglycemic [62] D'vlslon of 1968 activity; pharmaceutical compositions comprising said compounds and methods of producing hypoglycemic effects in mammals are provided; an illustrative em- [52] US. Cl. ..424/229, 424/251, 424/273 bodimem is 1 ]f i] 2 i i 3 b t i id fidi [51] Int. Cl. ..A6lk 27/00 [58] Field of Search ..424/229, 251, 273 8 Claims, N0 w g CROSS REFERENCE TO RELATED. APPLICATIONS *This is a divisional application of Ser. No. 770,102, filed Oct. 23, 1968, now US. Pat. No. 3,538,085, which, in turn, is a continuation-in-part application of Ser. No. 624,195, filed Mar. 20, 1967, now abandoned.

DETAILED DISCLOSURE v This invention relates to hypoglycemically active lphenyl-sulfonyl-2-irninowimidazolidines and l-phenylsulfonyl-2-imino-hexahydropyrimidines pharmaceutically acceptable acid: addition salts thereof, their production, pharmaceutical compositions containing them and a method'of producing ahypoglycemic effect comprising administration of such compounds.

More particular the invention relates to phenylsul fonamide derivatives of the formula 1 R4 2) s Ri R2 wherein n is (zero) or 1;

each of R, and R independently of the other, is

hydrogen or lower alkyl; each of R and R independently of the other, is hydrogen lower alkyl, or, if n is 0, form together the tetramethylene radical; R is alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, cycloalkyl,cycloalkenyl,or aralkyk and .X is-hydrogen, .fluoro, chloro, bromo, lower alkyl, lower alkoxy, loweralkylthio, acetyl or amino;

' and pharmaceutically acceptable acid addition salts thereof, which compounds on oral or parenteral administration have strong hypoglycemic activity. This fact is surprising, because itis known in the art that sulfanilylguanidinesand N-alkyl derivatives thereof of the formula wherein R is hydrogen or alkyl, and N-(lirnidazolin-Z-yl)-p-chlorophenylsulfonamide of the forhave no hypoglycemic activity.

The hypoglycemic activity of the compounds of the invention is furthermore surprising, because p-sub stit'uted l-phenylsulfonyl-2-imidazolidinones, e.g. of the formula have hyperglycemic activity, i.e. they increase the blood sugar level in mammals.

Moreover, in contracts to sulfanilylguanidines and N-sulfanilyl-N'-alkyl ureas, the compounds according to the invention are free from antibacterial activity.

These beneficial properties in combination with a favorable therapeutic index render the compounds of the invention well suited for the treatment of diabetes. in the compounds of Formula 1, R R R R R and X as lower alkyl groups can be an alkyl group of from one to four carbon atoms, e. g. the methyl, ethyl, propyl, isopropyl, butyl, i-butyl, sec. butyl or ten. butyl group. Furthermore R; can be, e.g. the following groups; as

alkyl group an alkyl group of from five to 12 carbon atoms, e.g. the pentyl, l-pentyl, 2,2-dimethypropyl, lmethylbutyl, l-ethylpropyl, 1,2-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl or dodecyl group; as alkenyl group an alkenyl group of from three to four carbon atoms, e.g. the allyl, l-methylallyl, 2-rnethylallyl or the 2'butenyl group; as alkoxyalkyl or alkylthioalkyl an alkyl group of from three to eight carbon atoms which is interrupted by an oxygen ether or a thioether bond, e .g. the 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 2-propoxyethyl, 3-propoxypropyl, 4-propoxybutyl, 2-ipropoxyethyl, 3-i-propoxyethyl, 4-i-propoxybutyl, 2- butoxyethyl, 3-butoxypropyl or the 4-butoxybutyl group as well as the corresponding thioether; as cycloalkyl group a saturated cyclic hydrocarbon group of from three to 10 carbon atoms, which can be substituted with a methyl or an ethyl group, e.g. the cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, ethylcyclohexyl, cycloheptyl, methylcycloheptyl, cyclooctyl, methylcyclooctyl, cyclononyl, cyclodecyl, adamantyl or the norbornyl group; as cycloalkenyl group an unsaturated cyclic hydrocarbon group of from 5 to 9 carbon atoms with one double bond, eg the Z-cyclopenten-l-yl, 2- cyclohexen l-yl; 40

ylalkyl group, e.g. the benzyl or the phenethyl group.

A preferred class of compounds of particular strong hypoglycemic activity and freedom from antibacterial activity are compounds of Formula la 1v, 1V4 H x' -so2-r-i N 41 wherein each of R';, and R'.,, independently of the other, is hydrogen or lower alkyl, R' is alkyl and cycloalkyl having at most five carbon atoms, and X is amino, chloro, methoxy and acetyl, and the pharmaceutically acceptable acid addition salts thereof.

According to a first process the compounds of Formula l are produced by reacting, optionally in the presence of an acid binding agent, a reactive functional derivative of a sulfonic acid of the formula masked amino group convertible into an amino group by hydrolysis, reduction or reductive cleavage, with a compound of the formula H-N N-Rs suitable the halides, particularly the chlorides, and the anhydrides of the formula The reaction is preferably performed in the presence of a water miscible or water non-miscible inert organic solvent in the presence or absence of water. Suitable inert organic solvents are, e.g., hydrocarbons such as benzene, toluene or xylene, ether-type solvents such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, and lower ketones such as acetone or methyl ethyl ketone. Inorganic bases or salts can be used as acid binding agents, e.g., an alkali hydroxide, acetate, hydrogen carbonate, carbonate and phosphate such as sodium hydroxide, sodium acetate, sodium hydrogen carbonate, sodium carbonate and sodium phosphate, or the corresponding potassium compounds. In addition, calcium oxide, calcium carbonate, calcium phosphate and magnesium carbonate can be used. Also organic bases such as pyridine, trimethylamine or triethylamine, N,N-diisopropylmethylamine or collidine are suitable. Used in excess, these can also serve as solvents.

A masked amino group X" of the reaction product is subsequently modified by hydrolysis, reduction or reductive cleavage depending on the type of the group X" into the free amino group to convert this product into a compound of Formula I.

Examples of masked amino groups X which can be converted by hydrolysis into the free amino group are acylamino groups such as the acetamido group; also lower alkoxycarbonylamino groups such as the ethoxycarbonylamino group; aryloxycarbonylamino groups such as the phenoxycarbonylamino group; or arylmethoxycarbonylamino groups such as the benzyloxycarbonylamino groups; or groups of the corresponding thiocarbonic acid derivatives. Further examples are substituted methyleneamino groups such as the benzy- Iideneamino or p-dimethylamino-benzylideneamino group.

(III) (Ila) The hydrolysis to liberate the amino group can be performed, eg in an acid medium such as by heating in dilute methanolic hydrochloric acid or, if X" is an alkoxycarbonylamino group, it can also be performed under mild alkaline conditions, e.g. with lN to 2N sodium hydroxide solution.

An example for a group X which can be converted into the amino group by reduction is the nitro group and examples of those groups which lead to the amino group by reductive cleavage are the phenylazo or pdimethylamino-phenylazo groups. In general, these radicals can be reduced catalytically, e.g. by means of hydrogen in the presence of Raney nickel, palladium or platinum charcoal, in an inert solvent such as ethanol. Other usual reduction processes apart from these can be used, for example, the reduction of nitro groups or the reductive cleavage of azo groups by means of iron in acetic or hydrochloric acid.

Examples of starting materials of Formula III respectively Illa wherein n is O are l-methyl-, l-ethyl-, lpropyl-, l-isopropyl-, l-butyl-, l-isobutyl-, I-sec. butyll-tert.butyl-, l-pentyl-, l-isopentyl-, l-(l,l-dimethylpropyl)-, l-cyclopropyl-, l-cyclopropylmethyl-, lcyclobutyl-, l-cyclobutylmethyl-, l-cycl0pentyl-, lcyclopentylmethyl-, l-cyclohexyl-, l-cyclohexylmethyl-, l-(2-cyclohexylethyl), l-cycloheptyl, cycloheptylmethyl, l-cyclo-octyland l-cyclo-octylmethyl-, l-cyclononyl-, l-cyclodecyl-, 2-cyclopentenl-yl-, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl-, 2-methyl- 2-cyclohexenl -yl-, 3-methyl-2-cyclohexenl -yl-, 3- methyl-S-isopropyl-2-cyclohexen-l-yland 4-cyclooctenl -yl-2-amino-2-imidazoline.

l-Methyl-, l-cyclohexyland l-(2-cyclohexylethyl)- 2-aminoimidazoline have been described in the literature.

Other compounds are obtained analogously, eg by starting from ethylenediamines substituted corresponding to the definition of R These N-substituted ethylenediamines are reacted, e.g. with carbon disulfide to form l-substituted 2-imidazolidine thiones. These are converted with methyl iodide into correspondingly substituted 2-methylthio-Z-imidazolinium iodides which, on reaction with ammonia, yield the desired compounds of Formula III respectively Illa. These compounds are obtained by another process by condensation of N-substituted ethylenediamines with cyanogen chloride or bromide. A third process consists in reacting an N-substituted ethylenediamine with a salt of S-methyl-isothiourea to form the corresponding salt of an N-(2-substituted aminoethyl)-guanide and heating this until the ring is closed to form the corresponding salt of a l-substituted Z-amino-imidazoline. In analogy to the production of the known homologous ldodecyl-2-aminoimidazoline, a fourth process is the reaction of the 2-imino-imidazolidine with a lower alkyl halide of suitable monocycloaliphatic halide.

Another process for the preparation of starting materials of Formula II] respectively Illa consists in reacting 2-chloropropionyl chloride with an amine NR -R,. The obtained amide is reacted with benzylamine to give N-R -(2-benzylamino)-propionamide which is reduced with lithium aluminum hydride to the corresponding N-R -W'-benzyl-l ,2- propylenediamine. The latter is debenzylated with palladium and hydrogen to N-R -l,2-propylenediamine, which in turn is reacted with cyanogen bromide to give l-R -2-amino-4-methyl-imidazoline. The preparation of l-R -2-amino-5-methyl-imidazoline is carried out by reacting 2-chloropropionyl chloride first with benzylamine to form 2-chloro-N-benzyl-propionarnide, which is reacted with an amine NH -R to the corresponding 2-R -amino-N-benzyl-propionamide. The latter is reduced with lithium aluminum hydride in tetrahydrofuran to give l-benzylamino-2-R aminopropane, which in turn is debenzylated with hydrogen and palladium to give l-amino-2-R -amino propane. This diamine is finally reacted with cyanogen bromide to form l-R,,-2-amino-S-methyl-imidazoline. Similarly Z-aminodmidazolines substituted at N and in 4- and 5- position are prepared analogously.

Starting materials of Formula III, respectively Illa, wherein n is l, i.e. substituted 2-imino-hexahydropyrimidines, are also known in the literature or can be prepared in analogy to processes for the preparation of the imidazolines described hereinbefore.

Compounds of Formula I can be prepared according to a second process by condensing and cyclizing a compound of the formula R4 2)n a "1 l wherein n, R R R R and R have the meanings as defined under Formula I and X" has the meaning as defined under Formula II, with a reactive functional derivative of cyanic acid, if necessary hydrolyzing or reducing the reaction'product obtained to transform the group X" into a free amino group and, if desired, converting the compound obtained into an acid addition salt.

Cyanogen halides, particularly cyanogen chloride and cyanogen bromide, or esters of cyanic acid, particularly the phenyl ester are suitable reactive functional derivatives of cyanic acid. The reaction is preferably performed in the presence of a water miscible or water non-miscible inert organic solvent in the presence or absence of water. Suitable inert organic solvents are, e.g., hydrocarbons such as benzene, toluene, or xylene, lower alkanols such as methanol or ethanol, ether-type liquids such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, lower ketones, such as acetone or methyl ethyl ketone, carbonic acid ester such as acetic acid ethyl ester, carbonic acid nitriles such as acetonitrile, or sulfones such as tetrahydrothiophene- 1,1-dioxide. The reaction can be performed in the presence or absence of an acid binding agent. As acid binding agents are suitable inorganic bases or salts, e.g. alkali hydroxides, alkali hydrogen carbonates, alkali carbonates or alkali phosphates such as the corresponding sodium or potassium compounds. Also suitable arev calcium carbonate, calcium phosphate and magnesium carbonate.

The hydrolysis or reduction of a masked amino group X" to the free amino group can be performed as described hereinbefore.

A first group of starting materials of Formula IV consists of N-(2-aminoethyl)-phenylsulfonamides, wherein phenyl is substituted in p-position by a group X" and the amino group is substituted by a group R These starting materials are prepared by reacting a correspondingly substituted 1-phenylsulfonyl-aziridine with a primary amine NH R Such aziridines have been described in the literature; e.g. 4'-(aziridinel -sulfonyl)-acetanilide is described by R. Lehmann et al., Bull. Soc. Chim. Belges. 55, 52-97 (1946); CA. 4l, 5475 f (1947) and l-phenylsulfonyl-aziridine by J. Nelles et al. Germ. Pat. No. 695,331 Further aziridines of this type can be prepared analogously.

A second group of starting materials of Formula lV corresponds to the first group, however has additionally a lower alkyl group R substituted in the ethylene moiety. These compounds are prepared by reacting a correspondingly substituted phenylsulfonyl chloride with a 2-alkyl-aziridine [A. Weissberger, Heterocyclic Compounds with Threeand Four-Membered Rings, Part 1, John Wiley & Sons lnc., London (1964)] in the presence of diluted sodium hydroxide solution. Substituted l-phenylsulfonyl-2-alkylaziridines are obtained which can be further reacted with primary amines NI-I -R as described hereinbefore.

Starting material of a third group of Formula IV wherein n is 0 and R and R together form the tetramethylene group are prepared by condensing 2- amino-cyclohexanol hydrochloride and N-acetylsulfanilyl chloride in pyridine to obtain N'-[2-(pacetamidophenylsulfonyloxy)-cyclohexyl]-N -acetylsulfanilamide and reacting the latter with a primary amine NH -R in ethanolic solution whereby the pacetarnidophenylsulfonyloxy group is replaced by the --NHR group.

Compounds of Formula I wherein n is O are produced according to a third process by condensing and cyclizing a compound of the formula wherein R R R and R have the meanings as defined in Formula I and X" has the meaning as defined in Formula II, with a compound of the formula EN (VI) wherein R has the meaning as defined in Formula I, or with an alkali or alkaline earth derivative thereof, if necessary hydrolyzing or reducing the reaction product obtained to convert the masked amino group X" into the free amino group and, if desired, converting the reaction product of Formula I, wherein n is 0, into an acid addition salt.

Suitable alkali and alkaline earth derivatives of Formula VI are the lithium sodium, potassium and calcium derivatives. The condensation is preferably performed in an ether-type liquid, e.g. in ether, tetrahydrofuran, dioxane, anisole or ethylenglycol-dimethylether.

The masked amino groups X" are the same as described hereinbefore and the conversion of these groups into the free amino group can be performed also as described hereinbefore.

wherein X" has the meaning as defined in Formula II with a reactive ester of a hydroxy compound of formula /I It, on it. N--lti JEN (VIII) wherein n, R,, R R R and R have the meanings as defined in Formula I, where applicable hydrolyzing or reducing the reaction product obtained to convert the masked amino group X into the free amino group and, if desired, converting the reaction product of Formula I into an acid addition salt.

Suitable reactive esters of hydroxy compounds of Formula VIII are e.g. halogenides, particularly chlorides and bromides, or sulfonic acid esters such as methanesulfonic acid or oand p-toluene-sulfonic acid esters. The condensation is performed preferably in a solvent miscible or not miscible with water and in the presence or absence of water. Suitable solvents are e.g. alkanols such as butanol, ether-type solvents, such as dioxane, diethyleneglycolmonomethylether, carbonic acid amides, such as N, N-dimethylformamide or sulfoxides such as dimethylsulfoxide. The condensation is advantageously carried out in the presence of an acid binding agent. Such acid binding agents are named in the first process of this invention. Furthermore also tertiary organic bases such as N,N-diisopropyl-ethylamine can be used.

Conversion of the masked amino group X" into the amino group can be performed as described hereinbefore.

Reactive esters of the hydroxy compounds of Formula VIII to be used as starting materials in this fourth process are prepared, e.g. by reacting l-alkylaziridines with cyanogen halides in dioxane whereby the halogenides of compounds of Formula VIII are obtained. Particularly useful in this reaction are cyanogen chloride and cyanogen bromide.

Compounds of Formula I are prepared according to a fifth process by condensing and cyclizing a reactive ester of a compound of the formula wherein n, R,, R R and R, have the meanings as defined in Formula I and X" has the meaning as defined in Formula II, with a primary amine NH R where applicable hydrolyzing or reducing the reaction product obtained to convert the masked amino group X" into the free amino group and, if desired, converting the reaction product of Formula I into an acid addition salt.

Suitable reactive esters of a hydroxy compound of Formula IX are, e.g. halogenides, particularly chlorides and bromides or sulfonic acid esters such as methanesulfonic acid or oand p-toluenesulfonic acid esters. The condensation is performed preferably in a solvent. Suitable solvents are such solvents as named in the fourth process of this invention.

Advantageously the reaction is performed in the presence of an acid binding agent. Such agents are named also in the fourth process of this invention. Furthermore and preferably suitable acid binding agents are the primary bases NI-I -R which are present in excess.

Conversion of the masked amino group X" into the free amino group can be performed as described hereinbefore.

Reactive esters of the hydroxy compounds of Formula IX to be used as starting materials in this fifth process are prepared, e.g. by reaction of cyanogen bromide with aziridine in ether to give N-(2-bromoethyl)-cyanamides. The latter are reacted in acetone in the presence of dilute sodium hydroxide solution with a correspondingly substituted phenylsulfonylchloride whereupon the correspondingly substituted N-(2- chloroethyl)-N-cyanophenylsulfonamides are obtained.

Compounds of Formula I are prepared according to a sixth process by reacting a compound of the formula wherein n, R,, R R R and R have the meanings as defined in Formula I, X has the meaning as defined in Formula II and R is arylmethyl, diarylmethyl or triarylmethyl, according to von Braun with a cyanogen halide, whereby R is replaced by the group -CaH, cyclizing the intermediate product obtained, where applicable hydrolyzing or reducing the reaction product obtained to convert the protected amino group X into the free amino group and, if desired, converting the reaction product of Formula I into an acid addition salt.

Suitable groups, R are e.g. the benzyl, benzhydryl, and the trityl group. Cyanogen chloride and cyanogen bromide are the preferred cyanogen halides used in this process. The reaction is advantageously performed in a solvent. Suitable solvents are e.g. hydrocarbons, such as benzene or toluene, or ether-type solvents such as ether, dioxane or tetrahydrofuran.

Conversion of the masked amino group X" into the free amino group can be performed as described hereinbefore.

Compounds of Formula X to be used as starting materials in this sixth process are prepared, e.g. by reacting in dioxane-water correspondingly substituted l-phenylsulfonylaziridines of Formula V with amines of the formula R (XI) wherein R and R have the meanings as defined in F ormula X.

Compounds of Formula I are prepared according to a seventh process by termal condensation and cyclization of addition salts of the formula R4 CH2); R:

. E 1' o wherein n, R,, R R R and R have the meanings as defined in Formula I, X" has the meaning as defined in Formula ll, and y is chloro, bromo or iodo, where applicable converting the masked amino group X" into the free amino group and, if desired, converting the reaction product of Formula I into an acid addition salt.

The thermal condensation and cyclization is performed by heating the addition salt with or without a solvent. Suitable solvents are inert liquids with a high boiling point, e.g. ethers, such as diethyleneglycoldimethylether, or carbonic acid amides, such as N,N- dimethyl-formamide.

Conversion of the masked amino group X" into the free amino group can be performed as described hereinbefore.

I Compounds of Formula Xll to be used as starting materials in this seventh process are prepared by reacting in water correspondingly substituted phenylsulfonyl chlorides with disodium cyanamide whereby the sodium derivatives of the corresponding N-cyano-phenylsulfonamides of Formula Xlll EN (x110 are formed. v The latter are reacted with acid addition salts of the formula R4 2)u R3 (i'i o Rt 111 Y N-Rt Y whereby the desired addition salts of Fonnula Xll are formed. The symbols n, R,, R R R R X." and Y i Formulas XIII and XIV have the meanings as defined in Formula Xll.

If desired, the compounds of Formula I obtained according to the processes of the invention are subsequently converted into pharmaceutically acceptable acid addition salts. Thesesalts are produced via conventional methods, e.g. by reacting the compounds of i0 benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.

The new compounds of the invention have been found to have hypoglycemic activities. These hypoglycemic effects are illustratively demonstrated in rats by orally administering the test compound to groups of five to six animals which have been not fed for 24 hours. Blood samples are taken from a vein of the animals and the blood sugar content is determined according to the method of Hagedorn-Jensen with an autoanalyser. Thus it is shown that the compounds of the invention on oral administration in amounts of from 20 to 400 mg/kg of bodyweight have significant hypoglycemic effects. Particular good blood sugar lowering properties have the following compounds: l-sulfanilyl-2-imino-2-n-butyl-imidazolidine, l-( pchlorophenylsulfonyl)-2-imino-3-n-butylimidazolidine, l-sulfani1yl-2-imino-3-n-butyl-5-ethylimidazolidine, l-sulfanilyl-2-imino-3-i-butylimidazolidine, l-sulfanilyl-2-imino-3-ipropylimidazolidine, l-sulfanilyl-2-imino-3-t-butylimidazolidine, l-sulfanilyl-2-imino-3-cyclopentylimidazolidine, l-sulfanilyl-2-imino-3-n-butyl-4-methylimidazolidine, l-sulfanilyl- 2-imino-3-sec-butyl-4- methyl-imidazolidine, l-sulfanilyl-2-imino-3-tbutyl-4- methyl-imidazolidine, 1-(p-methoxyphenyl-sulfonyl)- 2-imino-3-n-butyl-imidazolidine, l-(p-acetylphenylsulfonyl)2-imino-3-n-butyl-imidazolidine and lsulfanilyl-2-imino-3-t-butyl-4-methyl-iminozolidine.

The toxicity of the compounds of the invention on oral administration is of favorable low order.

Safety and effectiveness in humans has been demonstrated with 1-sulfanilyl-2-imino-3-n-butylimidazolidine on oral administration to patients suffering from diabetes.

The new active substances are preferably administered orally. The daily dosages vary between about LS and about 8 mg/kg of bodyweight for adult mammals. Suitable dosage units such as dragees, tablets or capsules preferably contain 50 500 mg of an active substance according to the invention, that is from 20 to percent of a compound of Formula I. Such dosage units are produced by combining the active substance with, e.g., solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin; laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with-the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights to form tablets or dragee cores. The latter are coated with, e.g. concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, eg to distinguish between varying dosages of active substance.

Other suitable dosage units for oral administration are hard or soft gelatine capsules. The former contain the active substance advantageously in the form of a granulate optionally in admixture with diluents such as maize starch, and lubricants such as talcum or magnesium stearate and, optionally stabilizing agents such as sodium metabisulfite (Na S O or ascorbic acid. In soft capsules the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, to which stabilizing agents can be added.

The following examples will serve to further typify the nature of the present invention but would not be construed as a limitation on the scope thereof. If not otherwise denoted by an alkyl group is meant a straight chain n-alkyl group.

EXAMPLE 1 a. 355 g of l-butyl-2-amino-2-imidazoline hydrochloride are added in portions to a solution of 198 g of sodium hydroxide in 2 liters of water. A solution of 443 g of p-nitrobenzene sulphochloride in 2 liters of acetone is then added dropwise within minutes and the red reaction mixture obtained is heated for 3 hours at 70, whereupon the acetone distills off. The residue is poured onto ice and the crude product is filtered off under suction. To purify, it is taken up in 2 liters of 2N hydrochloric acid, insoluble parts are filtered off and washed with water and the free base is precipitated from the hydrochloric acid solution by pouring it onto ice and concentrated ammonia. The precipitate is filtered off under suction, washed with water and recrystallized from benzene. The pure 1-(p-nitro-phenylsulphonyl)-2-imino-3-butylimidazolidine obtained melts at 9899.

b. 390 of the nitro compound produced according to (a) are dissolved in 15 liters of ethanol and the nitro group is reduced with hydrogen at and normal pressure in the presence of platinum charcoal. The catalyst is filtered off and the filter residue is washed with ethanol. The filtrate is concentrated in vacuo, 1 liter of 2N hydrochloric acid is added to the residue, the crude base, and the insoluble parts are filtered off and washed with water. The pure base is precipitated in crystalline form from the hydrochloric acid filtrate with 2N sodium hydroxide solution. It is filtered off under suction, washed with water and dried in vacuo at 90. The lsulphanilyl-2-imino-3-butyl-imidazolidine obtained melts at l7918l.

EXAMPLE 2 a. 60 ml of 5N sodium hydroxide and 30 g of ice are added to 20.5 g. of l-cyclohexyl-2-amino-2- imidazoline hydrochloride and a solution of 26 g of pnitro-benzene sulphochloride in 100 ml of acetone is added to the mixture. The crude 1-( p-nitrophenylsulphonyl)-2-imino-3-cyclohexyl-imidazoline immediately crystallizes. It is filtered off under suction, washed with water and recrystallized from a small amount of ethanol M.P. 160 161 with decomposition.

b. 35.2 g of the nitro compound produced according to a) are dissolved in 1 liter of ethanol and the solution is hydrogenated with hydrogen at 20 and normal pressure, in the presence of palladium charcoal (50 percent palladium), until no more hydrogen is taken up. The catalyst is then filtered off and washed with ethanol and the filtrate is evaporated in vacuo. Recrystallization of the residue from dioxane/water yields pure 1- sulphanilyl-2-imino-3-cyclohexyl-imidazolidine, MP. 18 ll83.

EXAMPLE 3 a. 10.0 g of l-butyl-2-amino-2-imidazoline hydrochloride are added to 5.5 g of sodium hydroxide in 55 ml of water. 15 g of p-acetylamino-benzene sulphochloride dissolved in 100 ml of warm acetone are added to the clear solution obtained whereupon the temperature of the reaction mixture rises and a thick, white precipitate is formed. The mixture is heated for half an hour at 90-95 and then concentrated in vacuo. The crystal slurry which remains is filtered off under suction, washed with water and recrystallized from 1 liter of ethanol. Colorless p-(2-imino-3-butyl-1- imidazolidinylsulphonyl)-acetanilide is obtained which melts at 243-244.

b. 15 g of the acetanilide derivative produced according to (a) are heated in 50 ml of 2N hydrochloric acid for 1 hour at The solution is then cooled to 20 and made alkaline with 2N sodium hydroxide solution. The precipitate formed is filtered off under suction and washed with water. The filter residue is recrystallized from ethanol whereupon l-sulphanilyl-Z- imino-3-butyl-imidazolidine is obtained, M.P. 179l 8 1.

EXAMPLE 4 a. 10.0 g of 1-butyl-2-amino-2-imidazoline hydrochloride are added to 5.5 g of sodium hydroxide in 55 ml of water. 12.5 g of N-methoxycarbonylsulphanil chloride in 100 ml of acetone are added to the clear solution obtained. The solution turns yellow for a short time whereupon a thick, colorless precipitate immediately forms. 100 ml of water are added to the mixture, the precipitate is filtered off and washed with water. Recrystallized from methanol, the pure p-(2-imino-3-butyl-1-imidazolidinylsulphonyl)- carbanilic acid ethyl ester obtained melts at l98200.

b. 17.7 g of the methoxycarbonyl compound produced according to (a) are refluxed for 1 hour in 100 ml of percent methanol containing 6 g of sodium hydroxide. The reaction mixture obtained is concentrated in vacuo and 50 ml of water are added. The crystalline precipitate formed is filtered off under suction and washed with ml of water. After recrystallization from ethanol, the 1-sulphanilyl-2-imino-3- butyl-imidazolidine obtained melts at 179-181.

EXAMPLE 5 4'-( 2-imino-3-sec. butyl-1-imidazolidinylsulphonyl)- acetanilide (M.P. 250-25l) is obtained analogously to example 3(a) from 10 g of l-sec. butyl-2-amino-2- imidazoline hydrochloride and 15 g of p-acetylaminobenzene sulphochloride. It is hydrolyzed according to example 3(a) to form l-sulphanilyl-2-imino-3-sec. butyl-imidazolidine, M.P. 173l 73.5.

EXAMPLE 6 a. 13.5 g of 1-methyl-2-amino-2-imidazoline hydrochloride are dissolved in ml of water and 14 g of sodium hydroxide are added. The solution of 23.4 g of p-acetylaminobenzene sulphochloride in 300 ml of acetone is added whereupon an exothermic reaction occurs and a thick crystal slurry precipitates. The mixture is refluxed for 1 hour, cooled and diluted with 250 EXAMPLE 7 Analogously to example (a), l-(p-acetamidophenylsulphonyl)-2-imino-3-ethyl-imidazolidine (which decomposes at 250) is obtained from 14.9 g of ,l-ethyl- 2-amino-2-imidazoline hydrochloride in 150 ml of water and g of sodium hydroxide solution with 23.4 g of p-acetylaminobenzene sulphochloride in 300 ml of acetone. It is hydrolyzed by heating at 80 for 30 minutes in 2N hydrochloric acid to form l-sulphanilyl- 2-imino-3-ethyl-imidazolidine, M.P. l72l 73.

EXAMPLE 8 l p-acetamidophenylsulphonyl )-2-imino-3- cyclohexen-l-yl-imidazolidine is obtained analogously to Example 6 from 20.2 g of 3-cyclohexen-l-yl-2- amino-2-imidazoline hydrochloride in 150 ml of water and 10 g of sodium hydroxide solution with 23.4 g of pacetamidobenzene sulphochloride in 300 ml of acetone. It is saponified by heating at 80 for 30 minutes in 2N hydrochloric acid to form l-sulphanilyl- 2-imino-3-cyclohexenl -yl-imidazolidine.

EXAMPLE 9 a. 31.3 g of N -(2-butylamino-ethyl)-N -acetylsulphanilamide are dissolved in 100 ml of 2 N sodium hydroxide solution and 10.6 g of cyanogen bromide is added with cooling at The crude product precipitates as crystals. It is filtered by suction after 30 minutes and recrystallized from N,N-dimethylformamide. The resulting 4'-(2-imino-3-butylimidazolidin-lylsulphonyl)-acetanilide melts at 243 244.

b. 33.8 g of the acetanilide obtained according to (a) are heated with 100 ml of 2 N hydrochloric acid for 1 hour to 80. The reaction mixture is then cooled to 20 and rendered alkaline with 2 N sodium hydroxide solution. The crude base which precipitates is removed by filtration, washed with water and recrystallized from ethanol. The resulting l-sulphanilyl-2-imino-3-butylimidazolidine melts at 179 181.

c. The starting compound for (a) is obtained as follows;

24.0 g of 4-(aziridin-l-ylsulphonyl)-acetanilide [cf. R. Lehmann et al., Bull.Soc.Chim.Belges 55, 52-97 (1946); C.A. 41, 5475 f (1947)] are dissolved in the cold in 100 ml of dioxane and 15 ml of water and the solution is added dropwise to 100 ml of butylamine. The reaction mixture is then refluxed for one hour and the excess butylamine as well as the dioxane is removed by distillation. The crystalline residue is recrystallized from ethyl acetate to yield pure N (2-butyl-aminoethyl)-N -acetyl):sulphanilamide melting at 97-98.

.14 EXAMPLE 10 a. Analogously to Example 9 (a), 4-(2imino-3- methylimidazolidinl-ylsulphonyl)-acetanilide having a melting point of 266 267 is obtained from 27.1 g of N-(Z-methyIamino-ethyl)-N-acetyl-sulphanilamide and 10.6 g of cyanogen bromide.

b. 29.6 g of the acetanilide obtained according to (a) are allowed to stand for 48 hours at 20 with 200 ml of 8 N ethanolic hydrochloric acid. The reaction mixture is then concentrated under vacuum, the crystalline residue is dissolved in water, and the solution is rendered alkaline with 2 N sodium hydroxide solution. The crude free base precipitates; it is filtered by suction and recrystallized from methanol/water to yield the pure l-sulphanilyl-2-imino-3-methyl-imidazolidine melting at 209 21 1.

c. The starting material used under (a), namely N- (2-methylamino-ethyl)-N-acetyl-sulphanilamide having a melting point of 102 (from ethyl acetate),

is obtained analogously to Example 9 (c) from 24 g of 4-aziridin-l-ylsulphonyl)-acetanilide and 100 ml of 40 percent aqueous methylamine.

EXAMPLE 1 l a. Analogously to Example 9 (a), 4'-(2-imino-3- tert.butyl-5-methyl-imidazolidinl-ylsulphonyl acetanilide, m.p. 227229, is obtained from 32.7 g of N-( l -methyl-2-tert. butylamino-ethyl )-N-acetylsulphanilamide and 10.6 g of cyanogen bromide.

b. 35.2 g of the acetanilide obtained according to (a) are added with stirring to g of 50 percent sulphuric acid which has been heated to 40. The mixture is heated for 2 hours at 50 and the the solution is poured with stirring into 750 ml of water. The crude product precipitates as the sulphate. The pH of the reaction mixture is adjusted to 6.3 with 10 N sodium hydroxide solution. The mixture, with the exception of a slight impurity, dissolves completely; it is stirred for 15 minutes with 2 g of active charcoal and filtered over Hyflo (purified diatomaceous earth). The filtrate is rendered alkaline with 10 N sodium hydroxide solution. The crude product precipitates. It is filtered, washed with water, dried at 90 and recrystallized from ethyl acetate. The resulting l-sulphanilyl-2-imino-3-tert. butyl-S- methylimidazolidine melts at l45l 46.

c. The starting compound mentioned under (a) is obtained as follows: A solution of 23.3 g of N-acetylsulphanilylchloride in 70 ml of acetone is added dropwise with stirring at l0 to 0 to 5.6 g of 2-methylaziridine in 30 ml of 4 N sodium hydroxide solution. The reaction is stirred at 0 for 2 more hours and then poured on to 400 ml of ice water. The resulting suspension is filtered, the precipitate, crude 4-(2-methylaziridin-l-ylsulphonyl)-acetanilide, is washed with water and then further processed immediately, since it EXAMPLE 12 a. A solution of 11.3 g of cyanogen bromide in 11.5 ml of ether is added dropwise during 10 minutes to a solution of 34 g of N -acetyl-N-[2-(3-ethoxypropylamine)-ethyl]-sulphanilamide in ml of dioxane. The resulting emulsion is refluxed in a bath of 70 for 1% hours. The reaction mixture is then concentrated. The residual yellow resin is dissolved in 175 ml of water, the color of the solution is removed with active charcoal, the solution is filtered and rendered alkaline at with 2 N sodium hydroxide solution. The precipitated crystals are separated by filtration, washed with water and recrystallized from ethanol, yielding 4- [2-imino-3-( 3-ethoxy-propyl]-imidazolidin- 1 ylsulphonyl)-acetanilide, m.p. 223 225.

b. 36.8 g of the acetanilide obtained according to (a) are dissolved while stirring for minutes in 200 ml of 8 N ethanolic hydrochloric acid. The solution is allowed to stand at room temperature for about 80 hours, and then concentrated. The residual brown resin is dissolved in water, the color of the solution is removed with active charcoal, and the solution is filtered. The clear filtrate which has been cooled with ice is carefully rendered alkaline with concentrated sodium hydroxide solution and the product which precipitates, crystallizing after several minutes, is separated by filtration, washed with water and dried. The resulting lsulphanilyl-2-imino-3-( 3-ethoxy-propyl )-imidazolidine melts after recrystallization from ethanol at 148 150.

0. The starting product for (a) is obtained as follows: 200 ml of 3-ethoxy-propylamine are heated to 80 and then while stirring 24.0 g of 4-(aziridin-lylsulphonyl)- acetanilide in 128 ml of dioxane/water (9:1 are added thereto during 30 minutes. The yellow solution is then heated at 80 for another 1% hours and then concentrated. The residual oil is purified by elution chromatography on a column of 400 g of silica gel. The N,N-bis-[2-(N -acety1-sulphanilamido)-ethyl]-3-ethoxy-propyl-amine is first eluted with chloroform/ethanol (9:1), and then the propylamino)-ethyll-sulphanilamide which is obtained as an oil is eluted with chloroform/ethanol (9:1) and (4:1).

EXAMPLE 13 a. Analogously to Example 12 (a), 4-(hexahydro-2- imino-benzimdazolin-1-ylsulphonyl)acetanilide is obtained from 42.6 g of N-(2-benzylamino-cyclohexyl)- N -acetyl-sulphanilamide and 10.6 g of cyanogen bromide.

b. 42.7 g of the crude acetanilide obtained according to (a) are hydrolyzed analogously to Example 10 (b) with 200 ml of ethanolic hydrochloric acid to yield 1- sulphanilyl-2-imino-3benzyl-hexahydrobenzimidazoline, m.p. 208- 210.

c. The starting material for (a) is obtained as follows: 15.15 g of 2-amino-cyclohexanol-hydrochloride are suspended in 120 ml of absolute pyridine and the suspension is cooled to 5. During half an hour 55.0 g of N-acetyl-sulphanilyl chloride are introduced into this mixture at 5 to 0. A slightly exothermic reaction takes place and the suspension dissolves. The solution is stirred for 4 hours at 0 5 in an ice bath and then poured on to 900 ml of ice water. A yellow sticky crude product precipitates; the crude product is extracted three times with ethyl acetate. The organic extract is washed once with water, twice with 6 N hydrochloric acid and twice with water, dried over sodium sulphate and concentrated. Recrystallization of the crystalline residue from methanol yields pure N -[2-(p-acetamide- 16 phenylsulphonyloxy)-cyclohexyl]-N-acetylsulphanilamide.

d. 50.9 g of the sulphanilamide obtained according to (c) are suspended in 250 ml of ethanol and treated with 157 g of benzylamine. The mixture dissolves and a slightly exothermic reaction takes place. The solution is allowed to stand for 2 hours at room temperature, it is then heated for 4 hours to 50 and finally concentrated. The residue is taken up in methylene chloride and concentrated ammonia and the organic phase is extracted with 2 N hydrochloric acid. The hydrochloric acid extract is purified with active charcoal and filtered. The filtrate is treated with ammonia; a resin precipitates. Several drops of methylene chloride are added to the resulting suspension and the resin is triturated; it then crystallizes. The crystals are filtered, washed with water and recrystallized from isopropanol/methylene chloride. N-(2-benzylamino-cyclohexyl)-N-acetylsulphanilamide having a melting point of 180 182 is obtained.

EXAMPLE 14 a. Analogously to Example 9 (a), starting from 28.5 g of N-(2-ethylamino-ethyl)-N-acetyl-sulphanilamide, m.p. 108 110 (from ethyl acetate), and 10.6 g of cyanogen bromide, 4'-( 2-imino-3-ethyl-imidazolidin-1- ylsulphonyl)-acetanilide, m.p. 267 269 (from ethanol), is obtained. 31.0 g of the latter are hydrolyzed analogously to Example 9 (b) with 100 ml of 2 N hydrochloric acid to give l-sulphanilyl-Z-imino- 3-ethyl-imidzolidine, m.p. 171 172 (from methanol/water), as end product.

(b) The starting material for (a) is obtained analogously to Example 9 (c) from 24.0 g of 4- (aziridin-1-ylsulphonyl)-acetani1ide and 100 ml of ethylamine.

Example 15 a. Analogously to Example 9 (a), starting from 29.7 g of N-(2-allylamino-ethyl)-N-acetyl-sulphanilamide (crude product), and 10.6 g of cyanogen bromide, 4'- (2-imino-3-allyl-imidazolidin-1-ylsulphonyl)-acetanilide, m.p. 247- 249 (from methanol), is obtained. 32.2 g of the latter are hydrolyzed analogously to Example 9 (b) with 100 ml of 2 N hydrochloric acid to give 1sulphanilyl-Z-imino-3allyl-imidazolidine, m.p. 158 160 (from methanol/water), as end product.

b. The starting material for (a) is obtained analogously to Example 9(c) from 24.0 g of 4- (aziridin-1ylsulphonyl)-acetanilide and ml of allylamine.

EXAMPLE 16 a. Analogously to Example 9(a), starting from 29.9 g of N-(2-propylamino-ethy1)-N-acetyl-sulphaniliamide, m.p. 89 90 (from ethyl acetate), and 10.6 g of cyanogen bromide, 4-(2-imino-3propyl-imidazolidinlylsulphonyl)-acetanilide, m.p. 253 255, obtained. 32.4 g of the latter are hydrolyzed analogously to Example 10 (b) with 8 N ethanolic hydrochloric acid to give lsuphanilyl-Z-imino-3-propyl-imidazolidine, m.p. 164 4 166 (from methanol), as end product.

b. The starting material for (a) is obtained analogously to Example 9 (c) from 24.4 g of 4'- (aziridin-1-ylsu1phonyl)-acetanilide and 100 ml of propylamine.

' EXAMPLE 17 a. Analogously to Example 9 (a), starting from 29.9 g

EXAMPLE 18 a. Analogously to Example 9 (a), starting from 31.3 g of N-( 2-isobutylamino-ethyl )-N -acetyl-sulphanilamide, m.p. 70 73 (from ethyl acetate/ether), and 10.6 g of cyanogen bromide, 4-(2-imino-3 1sobutylimidazolidin-1-ylsulphonyl)-acetanilide, m.p. 264-265 (from methanol), is obtained. 33.8 g of the latter are hydrolyzed analogously to Example (b) with 200 ml of 8 N ethanolic hydrochloric acid to give 1- sulphanilyl-2imino-3-isobutyl-imidazolidine, m.p. 146

147 (from methanol), as end product.

b. The starting material for (a) is obtained analogously to Example9 (c) from 27.6 g of N -(2- chloro-ethyl)-N -acetyl-sulphanilamide and 100 ml of isobutylamine.

EXAMPLE 19 a. Analogously to Example 9 (a), starting from 31.3 g of N-(2-secbutylamino-ethyl)-N-acetyl-sulphanilamide, m.p. 70-72, and 10.6 g of cyanogen bromide, 4 2-imino-3-sec.butylimidazolidinl -ylsulphonyl acetanilide, m.p. 265-266 (from methanol, is obtained 33.8 g of the latter are hydrolyzed analogously to Example 10 (b) with 200 ml of 8 N ethanolic hydrochloric acid to yield the end product, 1- sulphanilyl-2-imino-3-sec.butyl-imidazolidine, m.p. 173-173.5 (from methanol).

b. The starting material for (a) is obtained analogously to Example 9 (c) from 24.0 g of 4'- (aziridin-1-ylsulphonyl)-acetanilide and 100 ml of sec.butylamine.

EXAMPLE 20 a. Analogously to Example 9 (a), starting fi'om 31.3 g of N-( 2-tert.butylamino-ethyl )-N-acetyl-sulphani lamide, m.p. 98101 (from ethyl acetate), and 6.5 g of cyanogen chloride in place of cyanogen bromide, 4-( 2 -mino-3-tert.butyl-imidazolidin-l-ylsulphonyD-acetanilide, m.p. 245247 (from methanol/water), is obtained. 33.8 g of the latter are hydrolyzed analogously to Example 9'(b) with 100 ml of 2 N hydrochloric acid to yield l-sulphanilyl-2-imino-3-tert.butylimidazolidine, m.p. l87189 (from methanol/waterLas end product.

b. The starting material for (a) is obtained analogously to Example 9 (c) from 24.0 g of 4'- (aziridin-l-ylsulphonyl)-acetani1ide and ml of tert. butylamine.

EXAMPLE 21 a. Analogously to Example 9 (a), starting from 32.7 g of N -(2-pentylamino-ethyl)-N"-acetyl-sulphanilamide, m.p. 103-l04 (from ethyl acetate), and 10.6 g of cyanogen bromide, 4-(2-imino-3-pentyl-imidazolidin- 1-ylsulphonyl)-acetanilide, m.p. 248250 (from methanol), is obtained. 35.2 g of the latter are hydrolyzed analogously to Example 9 (b) with 100 ml of 2 N hydrochloric acid to obtain 1 sulphanilyl-Z- imino-3-pentylimidazolidine, m.p. 167168 (from methanol), as end product.

b. The starting material is obtained analogously to Example 9 (c) from 24.0 g of 4-(aziridin-l-ylsulphonyl)-acetanilide and 100 ml of pentylamine.

EXAMPLE 22 a. Analogously to Example 9 (a), starting from 34.1 g of N-(2-hexylamino-ethyl)-N-acetyl-sulphanilamide, m.p. 9899 (from ethyl acetate), and 1 1.9 g of phenyl cyanate in place of cyanogen bromide, 4'-( 2-imino-3- imidazolidinl -ylsulphonyl)-acetanilide, m.p. 23623 8 is obtained. 36.6 g of the latter are hydrolyzed analogously to Example 10 (b) with 200 ml of ethanolic hydrochloric acid to obtain 1-sulphanilyl-2-imino-3- hexyl-imidazoline, m.p. 182183 as end product.

b. The starting material for (a) is obtained analogously to Example 9 (c) from 24.0 g of 4- (aziridin-1-ylsulphonyl)-acetanilide and 200 ml of hexylamine.

EXAMPLE 23 a. Analogously to Example 9 (a), starting from 36.9 g of N'-( 2-octylamino-ethyl )-N-acetyl-sulphanilamide m.p. 83-84 (from ethyl acetate), and 10.6 g of cyanogen bromide, 4'-(2-imino-3-0cty1-imidazolidin-1- ylsulphonyl)-acetanilide, m.p. 229230 (from methanol), is obtained. 39.4 g of the latter are hydrolyzed analogously to Example 10 (b) with 200 ml of 8 N ethanolic hydrochloric acid to obtain 1- sulphanilyl-2-imino-3-octyl-imidazolidine, m.p. l43144, as end product.

b. The starting material for a) is obtained analogously to Example 9 (c) from 24.0 g of 4- (aziridin-1-ylsulphonyl)-acetanilide and ml of octylamine.

EXAMPLE 24 a. Analogously to Example 9 (a), starting from 39.7 g of N -(2-decylamino-ethyl)-N-acetyl-su1phanilamide, m.p. 87-88 (from ethyl acetate), and 1 1.9 g of phenyl cyanate in place of cyanogen bromide, 4'-( 2-imino-3- imidazolidin-1-ylsulphonyl)acetanilide, rn.p. 2162 1 7 is obtained. 42.2 g of the latter are hydrolyzed analogously to Example 10(b) with 200 ml of ethanolic hydrochloric acid to obtain l-sulphanilyl-2-imino-3- decyl-irnidazolidine, m.p. 1 l9-120.

b. The starting material for (a) is obtained analogously to Example 9 (c) form 24.0 g of 4'- (aziridin-1-ylsulphonyl)-acetanilide and 200 m1 of decylamine.

EXAMPLE 25 a. Analogously to Example 9 (a), starting from 42.5 g of N -(dodecylamino-ethyl)-N -acetyl-sulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4'-(2 -imino-3-dodecyl-imidazolidin-l-ylsulphonyl)acetanilide, m.p. 218-2l9 (from dioxane), is obtained. 45.0 g of the latter are hydrolyzed analogously to Example 10 (b) with 200 ml of ethanolic hydrochloric acid to obtain l-sulphanilyl-2-imino-3-dodecyl-imidazolidine, m.p. l l-l 1 1 (from ethyl acetate), as end product.

b. The starting material for (a) is obtained analogously to Example 9 (c) from 24.0 g of 4'- (aziridin-l-ylsulphonyl)-acetanilide and 200 ml of dodecylamine.

EXAMPLE 26 EXAMPLE 27 a. Analogously to Example 9 (a), starting from 33.9 g of N-(2-cyclohexylamino-ethyl)-N -acetyl-sulphanilamide, m.p. l35l36 (from ethyl acetate), and 10.6 g of cyanogen bromide, 4'-(2-imino-3-cyclohexylimidazolidin-l-ylsulphonyl)-acetanilide, m.p. 283284 (from methanol), is obtained. 36.4 g of the latter are hydrolyzed analogously to Example 9 (b) with 100 ml of 2 N hydrochloric acid to obtain l-sulphanilyl-2- imino-3-cyclohexyl-imidazolidine, m.p. l78l79, as end product.

b. The starting material for (a) is obtained analogously to Example 9 (c) from 24.0 g of 4'- (aziridin-l-ylsulphonyl)-acetanilide and 100 ml of cyclohexylamine.

EXAMPLE 28 a. Analogously to Example 9 (a), starting from 33.7 g of N-[2-( 3-cyclohexenl -ylamino)-ethyl ]-N-acetylsulphanilamide, m.p. l21l22, and 10.6 g of cyanogen bromide, 4'-[2-imino-3-( 3-cyclohexen-l-yl)- imidazolidin-l-ylsulphenyl]-acetanilide, m.p. 283284 is obtained. 36.2 g of the latter are hydrolyzed analogously to Example (b) with 200 ml of 8 N ethanolic hydrochloric acid to obtain l-sulphanilyl-Z- imino-3-(3-cyclohexen-l-yl)-imidazolidine, m.p. 172l 73 (from methanol), as end product.

b. The starting material for (a) is obtained and analogously to Example 9 (c) from 24.0 g of 4'- (aziridin-l-ylsulphonyl)-acetanilide and 100 ml of (3- cyclohexenl -y] )-amine.

EXAMPLE 29 a. Analogously to Example 9 (a), starting from 39.0 g of N-[2-( l-adamantylamino)-ethyl]-N-acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromide 4-[2-imino-3-(l-adamanty|)- imidazolidinl -ylsulphonyl]-acetanilide, m.p. 240243 is obtained. 29.6 g of the latter are hydrolyzed analogously to Example 10 (b) with 200 ml of 8 N ethanolic hydrochloric acid to obtain l-sulphanilyl-2- imino-3-( l-adamantyl)-imidazolidine, m.p. 240-243, as end product.

b. The starting material for (a) is obtained analogously to Example 9 (c) from 24.0 g of 4'- (aziridin-l-ylsulphonyl)-acetanilide and 15.0 g of lamino-adamantane.

EXAMPLE 30 a. Analogously to Example 12 (a), starting from 33.1 g of N -[2-( 2-methylthio-ethylamino)-ethyl ]-N-acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4-[2-imino-3-(2-methylthioethyl )-imidazolidin- 1 -ylsulphonyl]-acetanilide, m.p. 257-259, is obtained. 35.6 g of the latter are hydrolyzed analogously to Example 12 (b) with 200 ml of 8 N ethanolic hydrochloric acid to obtain 1- sulphanilyl-2-imino-3-(2-methyl-thio-ethyl)- imidazolidine, m.p. l53l 55, as end product.

b. The starting material for (a) is obtained analogously to Example 12 (c) from 24.0 g of 4'- (aziridin-l-ylsulphonyl)-acetanilide and 200 ml of 2- methylthio-ethylamine.

EXAMPLE 31 a. Analogously to Example 12 (a), starting from 31.5 g of N-[2-(2-methoxy-ethylamino)-ethyl]-N-acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4-[2-imino-3-(2-methoxy-ethyl)- imidazolidin-l-ylsulphonyl]-acetanilide, m.p. 230-232 is obtained. 34.0 g of the latter are hydrolyzed analogously to Example 12 (b) with 200 ml of 8 N ethanolic hydrochloric acid to obtain l-sulphanilyl-2- imino-3-(2-methoxy-ethyl)-imidazolidine, m.p. l59-16l, as end product.

b. The starting material for (a) is obtained analogously to Example 12 (c) from 24.0 g of 4- (aziridin-l-ylsulphonyl)-acetanilide and 200 ml of 2- methoxy-ethylamine.

EXAMPLE 3 2 a. Analogously to Example 12 (a), starting from 32.9 g of N-[2-(3-methoxy-propylamine)-ethyl]-N"-acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4'-[2-imino-3-(3-methoxy-propyl)- imidazolidin-l-ylsulphonyl]-acetanilide, m.p. 233235 is obtained. 35.4 g of the latter are hydrolyzed analogously to Example 12 (b) with 200 ml of 8 N ethanolic hydrochloric acid to obtain l-sulphanilyl-2- imino-3-( 3-methoxy-propyl )-imidazolidine, m.p. l32l 34, as end product.

b. The starting material for (a) is obtained analogously to Example 12 (c) from 24.0 g of 4- (aziridin-l-ylsulphonyl)-acetanilide and 200 ml of 3- methoxy-propylamine.

1 EXAMPLE 33 a. Analogously to Example 12 (a), starting from 35.7 g of N -[2-(3-isopropoxy-propylamino)-ethyl]-N acetyl-sulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4'-[2-imino-3-(3-isopropoxypropyl )-imidazolidinl -ylsulphonyl l-acetanilide, m.p.

224226, is obtained. 38.2 g of the latter are hydrolyzed analogously to Example 12 (b) with 200 ml of ethanolic hydrochloric acid to obtain l-sulphanilyl- 2-imino-3-( 3-isopropoxy-propyl )-imidazolidine, m.p. l33l 35, as end product.

b. The starting material .for (a) is obtained analogously to Example 12 (c) from 24.0 g of 4- (aziridin-l-ylsulphonyl)-acetanilide and 200 ml of 3- isopropoxy-propylamine.

EXAMPLE 34 a. Analogously to Example 12 (a), starting from 37.1 g of N-[2-(3-butoxy-propylamine)-ethyl]-N -acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4'-[ 2-imino-3-( 3-butoxy-propyl imidazolidinl -ylsulphonyl l-acetanilide, m.p. 2 l -2 l 2 is obtained. 39.6 g of the latter are hydrolyzed analogously to Example 12 (b) with 200 ml of 8 N ethanolic hydrochloric acid to obtain l-sulphanilyl-2- imino-3-(3-butoxypropyl)-imidazolidine, m.p. l26-l2 8, as end product.

b. The starting material for (a) is obtained analogously to Example 12 (c) from 24.0 g of 4- (aziridin-l-ylsulphonyl)-acetanilide and 200 ml of 3- butoxy-propylamine.

EXAMPLE 35 a. Analogously to Example 9 (a), starting from 28.5 g of N l-methyl-Z-methyIamine-ethyl )-N-acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4-(2-imino-3,5-dimethylimidazolidin-l-ylsulphonyl)-acetanilide, mp 25 826O is obtained. 31.0 g of the latter are hydrolyzed analogouslyto Example ll(b) with 125 g of 50 percent sulphuric acid to obtain l-sulphanilyl-2-imino-3,5- dimethyl-imidazolidine, m.p. l96l97, as end product. I

b. The starting material for (a) is obtained analogously to Example 9 (c) from 25.4 g of 4'-(2- methyl-aziridin-l-yl-sulphonyl)-acetanilide [cf. Example ll c)] and 200 ml of 33 percent methylamine in ethanol.

EXAMPLE 36 a. Analogously to Example 9(a), starting from 29.9 g

of N-( l-methyl 2ethylamine-ethyl)-N-acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromine, 4-(2-imino-3-ethyl-5-methylimidazolidin'l-y1sulph0nyl)-acetanilide, m.p. 229 230 is obtained. 32.4 g of the latter are hydrolyzed analogously to Example ll(b) with 125 g of 50 sulphuric acid to obtain l-sulphanilyl-2-imino-3-ethyl-5- methyl-imidazolidine, as end product. b. The starting material for (a) is obtained analogously to Example 9(c) from 25.4 g of 4-(2- methyl-aziridin-l-ylsulphonyl)-acetanilide [cf. Example 1l(c)] and 250ml of 20 percent ethylamine in benzene.

22 EXAMPLE 37 a. Analogously to Example 9(a), starting from 31.3 g of N-( l-methyl-2-propylarnine-ethyl )-N -acetylsulphanilamide, m.p. l62-l63, and 10.6 g of cyanogen bromide, 4'-(2-imino-3-propyl-5-methylimidazolidinl -ylsulphonyl)-acetanilide, m.p. 254-255 is obtained. 33.8 g of the latter are hydrolyzed analogously to Example 1 1(b) with 125 g of 50 percent sulphuric acid to obtain l-sulphanilyl-2-imino-3- propyl-5-methyl'imidazolidine, m.p. 146-148, as end product.

b. The starting material for (a) is obtained analogously to Example 9(c) from 25.4 g of 4'-(2- methyl-aziridinl -yl-sulphonyl )-acetanilide [cf. Example ll (c)] andlOOml of propylamine.

EXAMPLE 3 8 EXAMPLE 39 a. Analogously to Example 9(a), starting from 32.7 g of N l-methyl-2-sec.butylamine-ethyl )-N-acetylsulphanilamide, m.p. ll8-l20, and 10.6 g of cyanogen bromide, 4'-(2-imino13-sec.butyl-5-methylimidazolidinl -ylsulphonyl)-acetanilide, m.p.242244 is obtained. 35.2 g of the latter are hydrolyzed analogously to Example ll(b) with 125 g of 50 percent sulphuric acid to obtain l-sulphanilyl-2-imino-3- sec.butyl-S-methyl-imidazolidine, m.p. l94l95, as end product.

b. The starting material for (a) is obtained analogously to Example 9(c) from 25.4 g of 4-(2- methyl-aziridin-l-yl-sulphonyl)-acetanilide [cf. Example l l(c)] and ml of sec.butylamine.

EXAMPLE 40 a. Analogously to Example 9(a), starting from 34.1 g of N-( l-methyl-2-pentylamine-ethyl )-N -acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4'-(2-imino-3-pentyl-5-methylimidazolidinl -ylsulphonyl)-acetanilide, m.p. 228-229 is obtained. 36.4 g of the latter are hydrolyzed analogously to Example 1(b) with g of 50 percent sulphuric acid to obtain l-sulphanilyl-2-imino-3-pentyl-S-methyl-imidazolidine, m.p. l27-l28, as end product.

b. The starting material for (a) is obtained analogously to Example 9(c) from 25.4 g of 4'-(2- methyl-aziridin-l-yl-sulphonyl)-acetanilide [cf. Example l 1(c)] and 100 ml of pentylamine.

EXAMPLE 41 a. Analogously to Example 9(a), starting from 38.3 g of N-( l-methyl-2-octylamine-ethyl)-N-acetylsulphanilamide, m.p. 87, and 10.6 g of cyanogen bromide, 4'-( 2-imino-3-octyl-5-methyl-imidazolidinl -ylsulphonyl)-acetanilide, m.p. 2l52l6, is obtained. 40.6 g of the latter are hydrolyzed analogously to Example 11(b) with 125 g of 50 percent sulphuric acid to obtain l-sulphani1yl-2-imino-3-octyl-5-methylimidazolidine, m.p. l08109, as end product.

b. The starting material for (a) is obtained analogously to Example 9(c) from 25.4 g of 4'-(2- methyl-aziridin-l-ylsulphonyl)-acetanilide [cf. Example l 1(c)] and 100 ml of octylamine.

EXAMPLE 42 a. Analogously to Example 9(a), starting from 35.1 g of N-( l-methyl-2-cyclhexylamine-ethyl)-N-acetylsulphanilamide (crude product) and 10.6 g of cyanogen bromide, 4'-(2-imino-3-cyclohexyl-5- methyl-imidazolidinl -ylsulphonyl)-acetanilide, m.p. 235237, is obtained. 37.6 g of the latter are hydrolyzed analogously to Example 1 1(b) with 125 g of 50 percent sulphuric acid to obtain l-sulphanilyl-2- imino-3-cyclohexyl-5-methyl-imidazolidine, m.p. 2172l 8, as end product.

b. The starting material for (a) is obtained analogously to Example 9(c) from 25.4 g of 4'-(2- methyl-aziridin-l-yl-sulphonyl)-acetanilide [cf. Example ll(c)] and 100 ml of cyclohexylamine.

EXAMPLE 43 a. Analogously to Example 9(a), starting from 34.9 g of N 1-methyl-2-( 3-cyclohexenl-xlamine)-ethyl]- N-acetyl-sulphanilamide, m.p. l39141, and 10.6 g of cyanogen, bromide, 4'-[2-arnino-3-( 3-cyclohexenl yl)-5-methy1-imidazolidinl -yl-sulphonyl ]-acetanilide, m.p. 208209, is obtained. 37.4 g of the latter are hydrolyzed analogously to Example 1 Kb) with 125 g of 50 percent sulphuric acid to obtain l-sulphanilyl-2- imino-3-(3-cyclohexen-1-y1)-imidazolidine, m.p. 208209, as end product.

b. The starting material for (a) is obtained analogously to Example 9(c) from 25.4 g of 4'-(2- methyl-aziridin-1-yl-sulphonyl)-acetanilide [cf. Example ll(c) and 100 ml of (3-cyclohexon-l-yl)-amine.

EXAMPLE 44 a. A solution of 11.9 g of phenyl cyanate in 50 ml of ether is added during 10 minutes with cooling at 10 to a solution of 25.5 g of N-(2-cyclopropylamino-ethyl)- sulphanilamide in 100 ml of dioxane. The resulting suspension is refluxed for 1% hours and then concentrated under vacuum. The residue is treated with methylene chloride and 2 N sodium hydroxide solution. The insoluble crude product is separated by filtration; the organic phase of the filtrate is separated, dried over sodium sulphate and concentrated under vacuum. The residue is combined with the crude product obtained above and the mixture is recrystallized form methanol to yield l-sulphanil-2-imino-3-cyclopropy1- imidazolidine melting at 202-204.

The starting material is produced as follows:

b. 7.1 g of l-sulphanilyl-aziridine, m.p. l24-l26, produced by catalytic reduction of l-(p-nitro-phenylsulphonyl)-aziridine with Raney nickel in dioxane cf. R. Lehmann et al., Bull.Soc.Chim.Belges 55, 52 (1946)] ml of dioxane and this solution is added dropwise during 1 hour to 18.2 g of boiling cyclopropylamine. The mixture is refluxed for another 2 hours. The excess cyclopropylamine is then removed by distillation and the reaction mixture is concentrated under vacuum. The residue is recrystallized from ethyl acetate to obtain N-(2-cyclopropylaminoethyl )-sulphanilamide, m.p. 9 l-94.

EXAMPLE 45 a. Analogously to Example 44 (a), starting from 27.1 g of N-(2-butylamino-ethyl)-sulphanilamide, m.p. 7678, and a solution of 11.9 g of phenyl cyanate in 50 ml of ether, lsulphanilyl-2-imino-3-butylimidazolidine, m.p. 179-18l, is obtained.

The starting material is produced as follows:

b. 31.3 g of N-(2-butylamino-ethyl)-N-acetylsulphanilamide are shaken with 300 ml of ethanolic hydrochloric acid. First of all the crystals dissolve and then afier an interval of several minutes, crystals again precipitate. The suspension is allowed to stand for 16 hours at room temperature and then concentrated under vacuum. The residue is dissolved in a little water, and carefully adjusted to a pH of 8 with 2 N sodium hydroxide solution, whereby the solution becomes milky turbid. The solution is extracted three times, using 200 ml of chloroform each time. The chloroform solution is washed with a little water, dried with sodium sulphate and concentrated. The residue is recrystallized from ethyl acetate, to obtain N-(2-butylaminoethyl)-sulphanilamide melting at 7678.

EXAMPLE 46 Analogously to Example 44(a), starting from 28.3 g of N-(2-cyclopentylamino-ethyl)-sulphanilarnide, the hydrochloride of which melts at 190191, and a solution of 11.9 g of phenyl cyanate in 50 ml of ether, 1- sulphanilyl-Z-imino-3-cyclopentyl-imidazolidine, m.p. l92-l93, is obtained.

The starting material is produced analogously to Example 45(b) from 32.5 g of N -(2-cyclopentylaminoethyl)-N-acetyl-sulphanilamide [cf. Example 26(a)] and 300 ml of ethanolic hydrochloric acid.

EXAMPLE 47 27.1 g of N-(2-butylarnino-ethyl)-sulphanilamide are dissolved in ml of 2 N sodium hydroxide; 10.6 g of cyanogen bromide are added thereto. Crystals precipitate. The reaction mixture is stirred at room temperature for one hour and then the crystals are filtered. Recrystallization of the crude product from methanol yields pure l-sulphanilyl-2-imino-3-butylimidazolidine, m.p. 179-181.

EXAMPLE 48 Analogously to Example 47, starting from 120 ml of 2 N sodium hydroxide solution, the following are obtained:

a. with N-(cyclopropylamino-ethyl)-sulphanilamide and 10.6 g of cyanogen bromide, 1-sulphanilyl-2- m.p. 202-2o4,

EXAMPLE 49 A solution of 10.6 g ofcyanogen bromide in 50 ml of absolute ether is added with stirring during 30 minutes at to 5 toa solution of 14.6 g of butylamine in 100 ml. of absolute ether. The reaction mixture is stirred 30 minutes longer and the precipitated butylamine-hydrobromide is then removed by filtration. While cooling is continued, a suspension of 2.8 g of sodium hydride in 40 ml of absolute ether is added to the filtrate, containing'the resultant butyl-cyanamide dissolved therein. Cooling to the same temperature is continued while the suspension is stirred for another 30 minutes, and then 24.0 g of 4'-(aziridin-1-ylsulphonyl)- acetanilide is added to the resulting, suspended sodium derivative of the butylcyanamide. The mixture is warmed to room temperature and stirred for hours at this temperature. 2 N hydrochloric acid is then slowly added to the reaction mixture and the two phases which form are separated. The acidic aqueous phase is washed twice with ether, purified with active charcoal, filtered and rendered alkaline at 0 with concentrated sodium hydroxidesolution. The 4'-(2-imino 3-butyl-imidazolidin- 1 -ylsulphonyl)-acetanilide which precipitates is filtered and recrystallized from methanol; it then melts at 243244.

The acetanilide which is obtained is hydrolyzed analogously to Example 9(b) to l-sulphanilyl-Z-imino- 3-imino-3-butyl-imidazolidine, m.p. 179-18l.

EXAMPLE 50 Analogously to Example 49, the following are obtained: v

a. from 6.2 g of methylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the N-methyLcyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this yields with 24.0 g of 4'-(aziridin-l-yl-sulphonyl)-acetanilide, 4'-(2 -imino-3-methyl-imidazolidin-l-ylsulphonyl) acetanilide, m.p. 266267, which analogously to Example 10(b) is hydrolyzed to l-sulphani1yl-2-imino-3-methylimidazolidine, m.p. 2092l 1;

b. from 9.0 g of ethylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the N-ethylcyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this yields with 24.0 g of 4'-(aziridin-l-ylsulphonyl-acetanilide, 4-(2- imino-3-ethyl-imidazolidin-1-ylsulphonyl)-acetanilide, m.p. 267-269, which is hydrolyzed according to Example 14 to l -sulphanilyl-2-imino-S-ethylimidazolidine',

c. from 1 1.8 g of propylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the propyl-cyanamide, which with 2.8 g of sodium hydride in 40 m1 of ether is converted to the sodium derivative; this yields with 24.0 g of 4 '-(aziridin-1-yl-sulphonyl)-acetanilide, 4'-(2 imino-3-propyl-imidazolidin-l-ylsulphanyD-acetani- (d) from 14.6 g of tert.butylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the tert.butyl-cyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this yields with 24.0 g of 4-(aziridin-l ylsulphonyl)-acetanilide, 4'-( 2-imino-3-tert.butylimidazolidin- 1 -ylsulphonyl acetanilide, m.p. 245-247, which is hydrolyzed according to Example 20 to l-sulphanilyl-2-imino-3- tert.butyl-imidazolidine, m.p. 187l 89;

e. from 17.0 g of cyclopentylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the cyclopentylcyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this yields with 24.0 g of 4'-(aziridin-1-ylsulphonyl)- acetanilide, 4'-( 2-imino-3-cyc1opentyl-imidazolidinl ylsulphonyl)-acetani lide, m.p. 261-263, which is hydrolyzed according to Example 26 to l-sulphanilyl- 2-imino-3-cyclopentyl-imidazolidine, m.p. l92-193; and

f. from 19.8 g of cyclohexylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the cyclohxyl-cyanamide which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this yields with 24.0 g of 4-(aziridin-l-ylsulphonyl)-acetanilide, 4'-( 2-imino-3-cyclohexyl-imidazolidin- 1 -ylsulphonylacetanilide, m.p. 283284, which is hydrolyzed according to Example 27 to 1-sulphanilyl-2-imino-3- cyclohexyl-imidazolidine, m.p. 178179.

EXAMPLE 51 While stirring and cooling to -5 to -l0, a solution of 14.6 g of butylamine in 100 ml of absolute ether is added dropwise to a solution of 10.6 g of cyanogen bromide in 50 ml of absolute ether. After several minutes the butylamine-hydrobromide precipitates. It is separated by filtration. 2.8 g of sodium hydride in 40 ml of absolute ether are added in portions to the filtrate, in which the butyl-cyanamide is dissolved. A precipitate forms. The suspension is diluted with 200 ml of absolute ether and 200 ml of dioxane, and then it is stirred for 10 minutes at room temperature. 19.8 g of 1- sulphanilyl-aziridine are then added, the grey suspension is stirred for 15 more hours and then 30 ml of 2 N hydrochloric acid are added. The organic phase is separated and extracted twice with 2 N hydrochloric acid. The aqueous acidic phases are combined, purified with active charcoal and filtered. The reaction mixture is neutralized with solid sodium hydrogen carbonate,

- whereby a brown resin precipitates. The resin is filtered lide, m.p. 25 3 255, which is hydrolyzed according to Example 8 to 1-sulphanilyl-2-imino-3- propylimidazolidine, m.p. 164-166;

over celite (purified diatomaceous earth) and the clear colorless solution is rendered alkaline with concentrated sodium hydroxide solution. The reaction mixture is allowed to stand for one hour at 0, the precipitated crystals are filtered and recrystallized from ethanol. 1- sulphanilyl-2-imino-3-butylimidazolidine, m.p. 179l 8 1, is obtained.

EXAMPLE 5 2 Analogously to Example 51, there are obtained:

a. from 6.2 g of methylamine in m1 of ether and 10.6 g of cyanogen bromide, the methyl-cyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 19.8 g of l-sulphanilyl-aziridine yields 1-sulphanilyl-2-imino-3- methyl-imidazolidine, m.p. 209-21 1;

b. from 9.0 g of ethylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the ethyl-cyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 19.8 g of l-sulphanilyl-aziridine yields l-sulphanilyl-2-imino-3- ethyl-imidazolidine, m.p. 171-l72;

c. from 1 1.8 g of propylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the propyl-cyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 19.8 g of l-sulphanilyl-aziridine yields l-sulphanilyl-2-imino-3- propyl-imidazolidine, m.p. 164166;

d. from 14.6 g of tert.butylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the tert.butyl-cyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 19.8 g of l-sulphanilyl-aziridine yields l-sulphanilyl-2- imino-3-tert.butyl-imidazolidine, m.p. 187-189;

e. from 17.0 g of cyclopentylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the cyclopentylcyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 19.8 g of l-sulphanilylaziridine yields 1- sulphanilyl-2-imino-3-cyclopentyl-imidazolidine, m.p. 192l93; and

f. from 19.8 g of cyclohexylamine in 100 ml of ether and 10.6 g of cyanogen bromide, the cyclohexyl-cyanamide, which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 19.8 g of l-sulphanilyl-aziridine yields l-sulphanilyl-Z- imino-3-cyclohexyl-imidazolidine, m.p. 178179.

EXAMPLE 53 9.9 g of 1-tert.butyl-aziridine [cf. A. Weissberger, Heterocyclic Compounds with Three and Four-Membered Rings, John Wiley & Sons Inc., London (1964), page 530] are dissolved in 60 ml of dioxane and treated with 10.6 g of cyanogen bromide. In an exothermic reaction a solution of N-( 2-bromo-ethyl)-N-tert.butylcyanamide is obtained, which is added dropwise with stirring to a solution of 21.4 g of 4-sulphamoylacetanilide in 100 ml of 1 N sodium hydroxide solution. The reaction mixture is refluxed for one hour and then concentrated under vacuum to half its volume. The crystals which precipitate are filtered, washed with water, dried at 60 under vacuum and recrystallized from ethyl acetate. The resulting 4-(2-imino-3-tert.butylimidazolidin-l-ylsulphonyl)-acetanilide melts at 245-247 and is hydrolyzed according to Example 20 to yield l-sulphanilyl 2-imino-3-tert.butylimidazolidine, m.p. 187-189.

EXAMPLE 54 this is hydrolyzed according to Example l( b) to lsulphanilyl-2-imino-3-methyl-imidazolidine, 209-21 1;

b. from 7.1 g of l-ethyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(Z-bromoethyl)-N-ethyl cyanamide, which with 21.4 g of 4- sulphamoyl-acetanilide in ml of 1 n sodium hydroxide solution yields 4'-(2-imino-3-ethylimidazolidinl -ylsulphonyl)-acetanilide, m.p. 267269 this is hydrolyzed according to Example 14 to 1- sulphanilyl-2-imino-3-ethyl-imidazolidine, m.p. 17l-172;

c. from 8.5 g of l-propyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-propyl-cyanamide, which with 21.4 g of 4'- sulphamoyl-acetanilide in 100 ml of 1 N sodium hydroxide solution yields 4-(2-imino-3-propylimidazolidin-1-ylsulphonyl)-acetanilide, mp. 25 3255 this is hydrolyzed according to Example 16 to lsulphanilyl-2-imino-3-propyl-imidazolidine, m.p. 164l66.

d. from 8.5 g of l-isopropyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-isopropyl-cyanamide, which with 21.4 g of 4'- sulphamoyl-acetanilide in 100 ml of 1 N sodium hydroxide solution yields 4'-(2-imino-3-isopropylimidazolidin-1-ylsulphonyl)-acetanilide, m.p. 253254 this is hydrolyzed according to Example 17 to lsulphanilyl-2-imin0-3-isopropyl-imidazolidine, m.p. 183-184;

e. from 9.9 g of l-isobutyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-isobutyl-cyanamide, which with 21.4 g of 4'- sulphamoyl-acetanilide in 100 ml of 1 N sodium hydroxide solution yields 4-(2-imino-3-isobutylimidazolidin- 1 -ylsulphonyl)-acetanilide, m.p. 264-265 this is hydrolyzed according to Example 18 to 1- sulphanilyl-2-imino-3-isobutyl-imidazolidine, m.p. 146-147;

f. from 9.9 g of 1-sec.butyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-sec.butyl-acyanamide, which with 21.4 g of 4'-sulphamoyl-acetanilide in 100 ml of l N sodium hydroxide solution yields 4'-(2-imino-3-sec.butylimidazolidin-l-ylsulphonyl)-acetanilide, m.p. 265-266 this is hydrolyzed according to Example 19 to 1- sulphanilyl-Z-imino-3-sec.butyl-imidazolidine, m.p. 173-173.5;

g. from 11.3 g of l-pentyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-pentyl-cyanamide, which with 21.4 g of 4- sulphamoyl-acetanilide in 100 ml of 1 N sodium hydroxide solution yields 4'-(2-imino-3-pentylimidazolidin-l-ylsulphonyl)-acetanilide, m.p. 248250 this is hydrolyzed according to Example 21 to 1- sulphanilyl-2-imino-3-pentyl-imidazolidine, m.p. l67-168;

h. from 12.7 g of l-hexyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-hexyl-cyanamide, which with 21.4 g of 4'- sulphamoyl-acetanilide in 100 ml of l N sodium hydroxide solution yields 4'-(2-imino-3-hexylimidazolidin-1-ylsulphonyl)-acetanilide, m.p. 236238 this is hydrolyzed according to Example 22 to 1- sulphanilyl-2-imino-3-hexyl-imidazolidine, m.p. 182-183;

i. from 11.1 gof l-cyclopentyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromo- 29 ethyl)-N-cyclopentyl-cyanamide, which with 21.4 g of 4'-sulphamoylcetanilide in 100 ml of 1 N sodium hydroxide solution yields .4'-(2-imino-3-cyclopentylimidazolidinl -ylsulphonyl )-acetanilide, mp. 26 l 263 this is hydrolyzed according to Example 26 to lsulphanilyl-2-imino-3-cyclopentyl-imidazolidine, m.p. 192l93; and

j. from 12.5 g of l-cyclohexyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-cyclohexyl-cyanamide, which with 21.4 g of 4-sulphamoyl-acetanilide in 100 ml of l N sodium hydroxide solution yields 4'-(2-imino-3-cyclohexylimidazolidinl -ylsulphonyl )-acetanilide, m.p. 283-284 this is hydrolyzed according to Example 27 to lsulphanilyl-2-imino-3-cyclohexyl-imidazolidine, m.p. l78-l79.

EXAMPLE 55 14.7 g of l-phenethyl-aziridine are dissolved in 60 ml of dixane and treated with 10.6 g of cyanogen bromide. In an exothermic reaction N-( 2-bromo-ethyl)-N- phenethyl-cyanamide is formed, which in the reaction solution is added with stirring to a solution of 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution. The reaction mixture is refluxed for one hour and then concentrated under vacuum. Water is added to the residue, and the resulting precipitate is filtered and recrystallized from ethyl acetate. The resulting lsulphaniyl-2-imino-3-phenethyl-imidazolidine melts at 123l24.

EXAMPLE 5 6 Analogously to Example 55, the following are obtained: I

a. from 5.7 g of l-methyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(Z-bromoethyl)-N-methyl-cyanamide, which with 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution yields l-sulphanilyl-2-imino-3-methylimidazolidine, m.p. 20921 l;

b. from 7.1 g of l-ethyl-aziridine and 10.6.g of cyanogen bromide in 60 ml of dioxane, N-(Z-bromoethyl)- N-ethyl-cyanamide, which with 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution yields l-sulphanilyl-2-imino-3-ethylimidazolidine, m.p, l7ll 72;

c. from 8.5 g of l-propyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-propyl-cyanamide, which with 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution yields 1 -sulphanilyl-2-imino-3-propylimidazolidine, m.p. 164l 66;

f. from 9.9 g of l-isobutyl-aziridine and 10.6 g of cyanogen bromide in ml of dioxane, N-(2-bromoethyl)-N-isobutyl-cyanamide, which with 17.2 g of sulphanilamide in ml of 1 N sodium hydroxide solution yields l-sulphanilyl-2-imino-3-isobutylimidazolidine, m.p. l46-l 47;

g. from 9.9 g of l-sec.butyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-sec.butyl-cyanamide, which with 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution yields l-sulphanilyl-2-imino-3-sec.butylimidazolidine, m.p. 173-l73.5;

h. from 11.3 g of l-pentyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-pentyl-cyanamide, which with 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution yields l-sulphanilyl-2-imino-3-pentylimidazolidine, m.p. l67-l 68;

i. from 12.7 g of l-hexyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-hexyl-cyanamide, which with 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution yields l-sulphanilyl-2-imino-3-hexylimidazolidine, m.p. l82l 83;

j. from 11.1 g of cyclopentyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-cyclopentyl-cyanamide, which with 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution yields l-sulphanilyl-2-imino-3-cyclopentylimidazolidine, m.p. l92-l 93; and

k. from 12.5 g of l-cyclohexyl-aziridine and 10.6 g of cyanogen bromide in 60 ml of dioxane, N-(2-bromoethyl)-N-cyclohexyl-cyanamide, which with 17.2 g of sulphanilamide in 100 ml of l N sodium hydroxide solution ,yields l-sulphanilyl-2-imino-3-cyclohexylimidazolidine, m.p. l78l 79.

EXAMPLE 57 A mixture of 16.0 g of-N-(2-chloro-ethyl)-N-tert.butyl-cyanamide, 5.6 g of potassium hydroxide and 17.2 g of sulphanilamide in 100 ml of diethylene glycol ether are heated for 30 minutes in a bath having a temperature of l70. The reaction mixture is then poured on to ice and the suspension is filtered. The filter residue is dissolved in 2 N hydrochloric acid, the color of the solution is removed by active charcoal, the solution is filtered and rendered alkaline with concentrated sodium hydroxide solution. The crystals which precipitate are separated by filtration, washed with water and recrystallized from ethanol. l-sulphanilyl-Z- imino-3-tert.butyl-imidazolidine, m.p. 188190, is obtained.

EXAMPLE 5 8 a. 34.6 g of N-(2-bromo-ethyl)-N-cyano-N-acetylsulphanilamide are dissolved in 500 ml of ethanol and 7.3 g of butylamine, and refluxed for 17 hours. The reaction mixture is concentrated and the residue is taken up in chloroform and 2 N hydrochloric acid. The acidic aqueous extract is rendered alkaline with concentrated sodium hydroxide solution. The crude product precipitates; it is separated by filtration and purified by recrystallization from ethanol and acetone. The resulting 4'-( 2-imino-3-butyl-imidazolidinl -ylsulphonyD-acetanilide melts at 249251. This acetanilide is hydrolyzed according to Example 9 (b) to 1-sulphanilyl-2-imino-3-butylimidazolidine, m.p. 179-1 81.

b. The sulphanilamide used as starting material can be produced as follows:

During 30 minutes a solution of 4.3 g of aziridine in 20 ml of ether is added dropwise at to a solution of 10.6 g of cyanogen bromide in 30 ml of ether. The resulting suspension is concentrated under vacuum at a bath temperature below 40. The residue is slurried in 60 ml of water, and a solution of 25 g of N-acetylsulphanilyl chloride in 190 ml of acetone is added to the resulting suspension. 4.5 g of sodium hydroxide in ml of water are then added dropwise thereto during 10 minutes and the resulting mixture is refluxed for 30 minutes. After cooling, the crude product crystallizes. It is separated by filtration. Another yield of the crude product is obtained when the filtrate is diluted with water; it is separated and combined with the first fraction. The two fractions are recrystallized from methanol to yield N-(2-bromo-ethyl)-N-cyano-N- acetyl-sulphanilamide melting at l77179.

EXAMPLE 59 Analogously to Example 58, starting from 34.6 g of N 2-bromo-ethyl )-N-cyano-N -acetyl-sulphanilamide in 500 ml of ethanol, the following are obtained:

a. with 31.0 g of methylamine, 4'-(2-imino-3- methylimidazolidin-l-ylsulphonyl)-acetanilide, m.p. 266267, which is hydrolyzed according to Example 10(b) to l-sulphanilyl-2-imino-3-methyl-imidazolidine, m.p. 20921 1;

b. with 45.0 g of ethylamine, 4-(2-imino-3- ethylimidazolidin-1-ylsulphonyl)-acetanilide, m.p. 267-269, which is hydrolyzed according to Example 14 to 1-sulphanilyl-2-imino-3-ethyl-imidazolidine, m.p. 17ll72',

c. with 59.0 g of propylamine, 4'-( 2-imino-3-propylimidazolidin-1-ylsulphonyl)-acetanilide, mp. 25 3-255 which is hydrolyzed according to example 16 to lsulphanilyl-2-imino-3-propyl-imidazolidine, m.p. l64l66;

d. with 59.0 g of isopropylamine, 4"-(2-imino-3- isopropyl-imidazolidin-1-ylsulphonyl)-acetanilide, m.p.

253-254, which is hydrolyzed according to- Example 17 to 1-sulphanilyl-2-imino-3-isopropyl-imidazolidine, m.p. l83-184;

e. with 73.0 g of isobutylamine, 4'-(2-imino-3-isobutyl-imidazolidin-1-ylsulphonyl)-acetanilide, m.p. 264265, which is hydrolyzed according to Example 18 to 1-sulphanilyl-2-imino-3-isobutyl-imidazolidine, m.p. 146-l47;

f. with 73.0 g of sec.butylamine, 4-(2-imino-3- sec.butyl-imidazolidin- 1 -ylsulphonyl )-acetanilide, m.p. 265-266, which is hydrolyzed according to Example 19 to 1-sulphanilyl-2-imino-3-sec.butyl-imidazolidine, m.p. l73173.5;

g. with 73.0 g of tert.butylamine, 4-(2-imino-3- tert.butyl-imidazolidinl -ylsulphonyl )-acetanilide, m.p. 245-247, which is hydrolyzed according to Example 20 to l-sulphanilyl-2-imino-3-tert.butyl-imidazolidine, m.p. 187-189;

h. with 87.0 g of pentylamine, 4-(2-imino-3-pentylimidazolidin-1-ylsulphonyl)-acetanilide, m.p. 248-250 which is hydrolyzed according to Example 21 to l- EXAMPLE 60 a. A solution of 35.0 g of N-(2-bromoethyl)-N- cyano-N -acetyl-sulphanilamide and 10.0 g of 3- methoxy-propylamine in 250 ml of butanol is refluxed for 1% hours. The mixture is then poured into a liter of ice water and extracted with methylene chloride. The aqueous phase is separated and the organic phase is extracted with 2 N hydrochloric acid. The acidic aqueous extract is rendered alkaline with concentrated sodium hydroxide solution. The crude product precipitates. It is filtered and recrystallized from acetone/ethanol, yielding 4' 2-imino-3-( 3-methoxy-propyl imidazolidinl -ylsulphonyl]-acetanilide, mp. 23 3235 b. 35.4 g of the acetanilide obtained according to a) are dissolved in 150 ml of 2 N hydrochloric acid and the solution is heated for 1 hour in a bath having a temperature of 7880. The solution is then cooled and rendered alkaline with concentrated sodium hydroxide solution. The crude product precipitates. It is filtered and recrystallized from ethanol. The resulting 1- sulphanilyl-2-imino-3-( 3-methoxy-propyl)- imidazolidine melts at l32-134.

EXAMPLE 61 a. 38.9 g of N-[2-(N-isopropyl-benzylamine)-ethyl]- N -acetyl-sulphanilamide are dissolved in 500 ml of benzene. 10.6 g of cyanogen bromide are added to the solution, the reaction mixture is stirred for 3 hours at room temperature and then concentrated. The residue is rendered alkaline with 2 N sodium hydroxide solution. Crystals precipitate which are washed with water andrecrystallized from methanol/ether. The resulting, pure 4'-( 2-imino-3-isopropyl-imidazolidinl -ylsulphonyl)-acetanilide melts at 253. The acetanilide obtained is hydrolyzed according to Example 17 to lsulphanilyl-2-imino-3-isopropyl-imidazolidine, m.p. 183-184.

The starting material is produced as follows:

b. 24.0 g of 4'-(aziridin-l-ylsulphonyl)-acetanilide are dissolved in 100 ml of dioxane and 20 ml of water, and, while stirring, are refluxed for 5 hours with 15.0 g of N-benzylisopropylamine. The reaction mixture is then concentrated. The resulting oil crystallizes in ethyl acetate. Recrystallized from ethyl acetate, the pure N'- [2-( N-isopropyl-benzylamino )-ethyl -N-acetylsulphanilamide melts at 86.

EXAMPLE 62 a. 37.45 g of the addition salt of N-cyano-N-acetylsulphanilamide and N-( 2-chloro-ethyl )-tert.butylamine are heated for 1 hour in a bath having a temperature of 145, whereby the slat melts. The reaction mixture is cooled, the resinous substance is triturated with 2 N hydrochloric acid, and the insoluble resin is separated from the solution by decantation. The solution is rendered alkaline with concentrated sodium hydroxide solution, the crude product which precipitates is separated by filtration, washed with water and recrystallized from ethanol. 4'-(2-imino-3-tert.butylimidazolidin-1-ylsulphonyl)-acetanilide, m.p. 242-244 is obtained, which is hydrolyzed according to Example 20 to l-sulphanilyl-2-imino-3-tert.butylimidazolidine, m.p. l87-1 89.

The starting material is obtained as follows;

b. To a solution of 8.6 g of disodium cyanamide in 100 ml of water, there are added during 30 minutes in portions, 23.3 g of N-acetylsulphanilyl chloride, which gradually dissolves in a slightly exothermic reaction. The solution is stirred for one hour at room temperature, whereby the sodium derivative of N-cyano-N- acetyl-sulphanilamide is formed. Then during minutes, 17.2 g of N-( 2-chloro-ethyl)-tert.butylaminehydrochloride are added in portions to the reaction mixture. After an interval of a few minutes, the addition salt of N -cyano-N -acetyl-sulphanilamide and N- (2-chloro-ethyl)-tert.butylamine precipitates. The salt is filtered, washedwith water and recrystallized from isopropanol; it then melts at l22l 24.

EXAMPLE 63 a. 15.5 g of l-butyl-2-imino-hexahydropyrimidine are dissolved in a solution of 4.8 g of sodium hydroxide in 100 ml of water. A solution of 25 g of N-acetylsulphanilyl chloride in 100 ml of acetone is added thereto. An exothermic reaction takes place and crystals precipitate. The mixture is heated 'for 15 minutes longer in a water bath and then cooled to 0. The precipitated crystals are separated by filtration and recrystallized from ethanol. 4'-(2-imino-3-butyl-hexyhydropyrimidin-l-ylsulphonyl)-acetanilide, m.p. l89-1 91, is obtained.

b. 35.2 g of the acetanilide obtained according to (a) are dissolved in 180 ml of 8 N ethanolic hydrochloric acid, and this solution is allowed to stand for 2days at room temperature. The reaction mixture is concentrated and the residue is dissolved in water. The solution is separated by filtration and rendered alkaline with sodium hydroxide solution. The crystals which precipitate are separated by filtration, washed with water and recrystallized from acetone/methanol, to yield l-sulphanilyl 2-imino-3-butyl-hexahydropyrimidine melting at l80183.

EXAMPLE 64 The following are produced analogously to Example 63 (a):

a. from 23.4 g of l-octyl-2-arnino-2-imidazolin hydrochloride and 12.0 g of sodium hydroxide in 120 ml of water with 15.0 g of N-acetyl-sulphanilyl chloride, which has been dissolved in 150 m1 of warm acetone, 4'-( 2-imino-3-octylimidazolidinl -ylsulphenyl)-acetanilide, m.p. 229230, which is hydrolyzed analogously to Example 63 (b) to 1-sulphanilyl-2- irnino-3-octyl-imidazolidine, m.p. 143-144;

b. from 26.2 g of l-decyl-2-amino-2-imidazoline hydrochloride and 12.0 g of sodium hydroxide in 120 ml of water with 15.0 g of N-acetyl-sulphanilyl chloride, which has been dissolved in 150 ml of warm acetone, 4-(2-imino-3-decylimidazolidin-1-ylsulph0nyl)-acetanilide, m.p. 216217, which is hydrolyzed analogously to Example 63 (b) to l-sulphanilyl-Z- imino-3-decyl-imidazolidine, m.p. 1 19l20;

c. from 29.0 g of 1-dodecyl-2-amino-2-imidazoline hydrochloride and 12.0 g of sodium hydroxide in 120 ml of water with 15.0 g of N-acetyl-sulphanilyl chloride, which has been dissolved in 150 ml of warm acetone, 4'-(2-imino-3-dodecylimidazolidin-1-ylsulphonyl)-acetanilide, m.p. 2l8-219, which is hydrolyzed analogously to Example 63 (b) to 1- sulphanilyl-Z-imine-3-dodecyl-imidazolidine, m.p. -l11;

d. from 22.6 g of l-phenethyl-2-amino-Z-imidazoline hydrochloride and 12.0 g of sodium hydroxide in ml of water with 15.0 g of N-acetyl-sulphanilyl chloride, which has been dissolved in ml of warm acetone, 4'-( 2-imino-3-phenethylimidazolidin- 1 -ylsulphonyl)-acetanilide (crude product), which is hydrolyzed analogously to Example 63 (b) to lsulphanilyl-Z-imino-3-phenethyl-imidazolidine, m.p. l23l24;

e. from 21.2 g of l-benzyl-2-amino-2-imidazoline hydrochloride and 12.0 g of sodium hydroxide in 120 ml of water with 15.0 g of N-acetyl-sulphanilyl chloride, which has been dissolved in 150 ml of warm acetone, 4'-(2-imino-3-benzylimidazolidin-1 -y1- sulphonyl)-acetanilide, m.p. 268269, which is hydrolyzed analogously to Example 63 (b) to 1- sulphanilyl-Z-imino-3-benZyl-irnidazo1idine, m.p. l70-l7l; and

f. from 25.6 g of l-(l-adamantyl)-2-amino-2- imidazoline hydrochloride and 12.0 g of sodium hydroxide in 120 ml of water with 15.0 g of N-acetylsulphanilyl chloride, which has been dissolved in 150 ml of warm acetone, 4'-[2-imino-3-(1-adamantyl)- imidazolidin 1 -ylsulphonyl]-acetanilide, m.p. 273-275 which is hydrolyzed analogously to Example 63 (b) to 1-sulphanilyl-2-imino-3-( l-adamantyl irnidazolidine, m.p. 240243.

EXAMPLE 65 13.2 g of cyanogen bromide in 220 ml of ether are added to 31.0 g of crude N-tert.butyl-l ,2- propanediamine-dihydrobromide. During 5 minutes, a solution of 11.4 g of sodium carbonate in 88 m1 of water is added in portions to the resulting mixture. The suspension obtained is stirred for 15 hours at room temperature and allowed to stand for 2 days. The aqueous layer, containing 1-tert.butyl-2-amino-4-methyl-2- imidazoline, is separated from the ether solution and the aqueous phase is diluted with water to dissolve the precipitated sodium bromide. To the aqueous solution, a solution of 23.8 g. of N-acetyl-sulphanilyl chloride in 220 ml of acetone is added and also a solution of 8.8 g of sodium hydroxide in 44 ml of water. The mixture is then refluxed for 30 minutes, cooled; the crude product which precipitates is separated by filtration and recrystallized from chloroform/ethanol. 4-(2-imino-3- tert.butyl-5-methyl-imidazolidinl -ylsulphenyl acetanilide,m.p. 238240, is obtained.

b. The acetanilide obtained according to (a) is hydrolyzed analogously to Example 63 (b) to 1- sulphanilyl-2-imino-3-tert.butyl-5-methylimidazolidine, m.p. l45146.

The starting product for (a) can be produced as follows:

c. 16.35 g of N-tert.butyl-2-chloro-proionamide [cf. .l.Am.Chem.Soc. 78, 6124 (1956)] and 25.0 g of benzylamine are heated at a bath temperature of 150170 for 3% hours. From the solution which is originally homogeneous, crystals precipitate. The reaction mixture is cooled and 150 ml of 2 N sodium hydroxide solution and chloroform are added thereto. The organic phase is separated, washed with water, dried and concentrated. The residue is distilled. After a first running of benzylamine, I N-tert.butyl-(2- benzylamine)-propionamide, b.p. 123-125/0.03 Torr, is obtained. The hydrochloride melts at 158l 62 d. A solution of 23.4 g of the amide obtained according to (c) in 80 ml of absolute tetrahydrofuran is added dropwise during 15 minutes to a suspension of 9.0 g of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran. The suspension is then refluxed for 38 hours. The color changes to raspberry red and during a period of 30 minutes back to grey again. The reaction mixture is cooled, the excess lithium aluminum hydride is decomposed, while cooling, with ethyl acetate, then with water and with methanol and the suspension is concentrated. The grey residue is extracted twice with boiling chloroform during 30 minutes and filtered. The combined chloroform solutions are dried over sodium sulphate and concentrated. The residual oil is distilled. N-tert.butyl-N'-benzyl-1,2-propane-diamine distills at 7286/0.005 Torr.

e. 34.0 g of 48 percent pure hydrogen bromide and 8.8 g of 5 percent palladium charcoal are added to 22.0 g of the amine obtained according to (d) in 440 ml of distilled ethanol. The mixture is hydrogenated at room temperature and normal pressure. After 95 percent of the calculated amount of hydrogen has been taken up, 8.8 g of 5 percent palladium charcoal are added and hydrogenation is continued. After 17 hours, the reaction mixture has taken up 98 percent of the calculated amount of hydrogen. The catalyst is removed by filtration, rinsed with ethanol, and the filtrate is concentrated. The residue, N-tert.butyl-l,2-propanediamine dihydrobromide, is used as crude product.

EXAMPLE 66 a. Analogously to Example 65 (a-b), the following end product is obtained:

From N-butyl-l,2-propanediamine and cyanogen bromide, 1-butyl-Z-amino-4-methyl-2-imdazoline hydrobromide (crude product), which with N-acetylsulphanilyl chloride yields 4-(2-imino-3-butyl-5- methyl-imidazolidinl -ylsulphonyl )-acetanilide, m.p. 243244, the hydroysis of which yields l-sulphanilyl- 2-imino-3-butyl-5-methyl-imidazolidine, m.p. 1251 2 6.

The starting material is obtained as follows:

b. While cooling well with ice, 12.7 g of 2- chloropropionyl chloride in 20 ml of chloroform are added dropwise during 30 minutes to a solution of 16.1 g of butylamine in 50 ml of chloroform. The resulting solution is allowed to stand for 15 hours at room temperature, then washed several times with water, and the organic phase is separated. The organic phase is dried over sodium sulphate and concentrated. Crude N- butyl-2-chloro-propionamide remains as residue.

c. Analogously to Example 65 (c-e), starting from the crude amide from (b) via the intermediate products N-butyl-2-benzylamino-propionamide, b.p. 15 l -l 54 /0.005 Torr and N-butyl-N-benzyl-l ,2- propanediamine, b.p. 98-104/0.04 Torr, N-butyl 1,2- propanediamine is obtained.

EXAMPLE 67 a. Analogously to Example 65 (a-b), the following end product is obtained:

From N-butyl-l,Z-butanediamine (crude product) and cyanogen bromide, 1-butyl-2-amino-4-ethyl-2- imidazolidine-dihydrobromide (crude product), which with N-acetyl-sulphanilyl chloride yields 4'-( 2-imino-3- butyl-5 -ethyl -imidazolidin-1-ylsu|phonyl)-acetanilide (crude product), m.p. 107-l 1 1, which is hydrolyzed to l-sulphanilyl-2-imino-3-butyl-5-ethylimidazolidine, m.p. l6ll63.

The starting material for (a) is produced as follows:

b. Analogously to Examples 66 (b) and 65 (c-e), starting from 2-chloro-butyryl chloride via the intermediate products N-butyl-2-chlorobutyramide (crude product), N-butyl-2-benzyl-amino-butyramide (crude product) and N-butyl-N-benzyl-1,2-butanediamine (crude product), N-butyl-l,Z-butanediamine is obtained.

EXAMPLE 68 Analogously to Example 63(a) the following end product ARE obtained;

a. from 24.0 of 1-(2-methylthio-ethyl)-2-amino-2- imidazoline hydrobromide (m.p. 138-140) and 12.0 g of sodium hydroxide in ml of water with 23.3 g of N-acetyl-sulphanilyl chloride, which has been dissolved in ml of warm acetone, 4-[2-imino-3-(2- methylthio-ethyl)-imidazolidin-1-ylsulphonyl]-acetanilide, m.p. 257259, which is hydrolyzed analogously to Example 63(b) to 1-sulphanilyl-2-imino-3-(2- methylthio-ethyl )-imidazolidine, m.p. 15 2 1 5 3.

The starting material is produced analogously to Example 65(a) from 13.4 g of N-(2-amino-ethyl)-2- methylthio-ethylamine and 10.6 g of cyanogen bromide;

b. from 22.4 g of l-(2-methoxy-ethyl)-2-amino-2- imidazoline hydrobromide (m.p. 141-144") and 12.0 g of sodium hydroxide in 120 ml of water with 23.3 g of N-acetyl-sulphanilyl chloride, which has been dissolved in 150 ml of warm acetone, 4'-[2-imino-3-(2-methoxyethyl)-imidazolidin-l-ylsulphonyl]-acetanilide, m.p. 230232, which is hydrolyzed analogously to Example 63(b) to l-sulphanilyl-2-imino-3-(2-methoxyethyl)-imidazolidine, m.p. 230-232.

The starting material is produced analogously to Example 65(a) from 1 1.8 g of N-(2-amino-ethyl)-2- methoxy-ethylamine and 10.6 g of cyanogen bromide;

c. from 23.8 of l-(3-methoxy-propyl)-2-amino-2- imidazoline hydrobromide (crude product) and 12.0 g of sodium hydroxide in 120 ml of water with 23.3 g of N-acetyl-sulphanilyl chloride, which has been dissolved in 150 ml of warm acetone, 4-[2-imino-3-(3-methoxypropyl)-imidazolidinl1-ylsulphonyl]-acetanilide, m. p.

230-232, which is hydrolyzed analogously to Example 63(b) to 1-sulphanilyl-2-imino-3-( 3-methoxypropyl)-imidazolidine, m.p. 132-l 34.

The starting material is produced analogously to Example 65(a) from 23.8 g. of N-(2-amino-ethyl)-3- methoxy-propylamine and 10.6 g of cyanogen bromide;

d. from 25.2 g of 1-(3-ethoxy-propy1)-2-amino-2- imidazoline hydrobromide (crude product) and 12.0 g of sodium hydroxide in 120 ml of water with 23.3 g of N-acetyl-sulphanilyl chloride, which has been dissolved in 150 ml of warm acetone, 4'-[2-imino-3-(3-ethoxypropyl)-imidazolidin-1-ylsulphonyll-acetanilide, m.p. 220-223; which is hydrolyzed analogously to Example 63(b) to l-sulphanilyl-2-imino-3-( 3-ethoxypropyl)-imidazolidine, m.p. l48-150.

The starting material is producedanalogously to Ex ample 65(a) from 14.6 g. of N-(2-amino-ethyl)-3- ethoxy-propylamine and 10.6 g of cyanogen bromide;

e. from 26.6 g of 1-(3-isopropoxy-propyl)-2-amino- 2-imidazo1ine hydrobromide (crude product) and 12.0 g of sodium hydroxide in 120 ml of water with 23.3 g of N-acetyl-sulphanilyl chloride, which has been dissolved in 150 ml of warm acetone, 4'-[2-imino-3-(3- isopropoxy-propyl )-imidazolidinl -ylsulphonyl acetanilide, m.p. 224226, which is hydrolyzed analogously to Example 63(b) to l-sulphanilyl-Z- imino-3-( 3-isopropoxy-propyl )-imidazolidine, m.p. 133-135.

The starting material is produced analogously to Example 65(a) from 16.0 g of N-(2-an1ino-ethy1)-3- isopropoxy-propylamine and 10.6 g of cyanogen bromide; and

f. from 28.0 g of 1-(3-butoxy-propy1)-2-amino-2- imidazoline hydrobromide (crude product) and 12.0 g of sodium hydroxide in 120 ml of water with 23.3 g of N-acetyl-sulphanilyl chloride, which has beendissolved in 150 ml of warm acetone, 4'-[2-imino-3-(3-butoxypropyl)-imidazolidin-1-ylsulphonyll-acetanilide, m.p. 2l0-212, which is hydrolyzed analogously to Example 63(b) to 1-sulphanilyl-2-imino-3-(,3-butoxypropyl)-imidazolidine, m.p. l26-128.

The starting material is produced analogously to Example 65(a) from 17.4 g of N-(2-amino-ethyl)-3-butoxy-propylamine and 10.6 g of cyanogen bromide.

EXAMPLE 69 a. Analogously to Example 9 (a), starting from 30.1 g of N-( 2-cyclohexylamino-ethyl )-p-nitrobenzenesulphonamide (crudeproduct) and 10.6 g of cyanogen bromide in 100 ml of 2 N sodium hydroxide solution, 1-(p-nitro-phenylsulphonyl)-2-imino-3- cyclohexyl-imidazolidine, m.p. 9899 (from benzene) is obtained.

1 b. 35.2 g of the nitro compound produced according to (a) are dissolved in one liter of ethanol, and, in the presence of palladium-charcoal (50 percent palladium), then hydrogenated at and normal pressure until cessation of the reaction. The catalyst is then removed by filtration, rinsed with ethanol, and the filtrate is concentrated under vacuum. Recrystallization of the residue from dioxane/water yields pure 1- sulphanilyl-2-imino 3-cyclohexyl-imidazolidine, m. p. 18l-l 83.

phenylsulphonyl)-aziridine and 150 ml of cyclohexylamine.

EXAMPLE a. 25.6 g of N-(2-propy1aminoethyl) are dissolved in 100 ml of 2 N sodium hydroxide solution and, while cooling at 20-30, 10.6 g of cyanogen bromide are added. The reaction mixture is allowed to stand for 10 minutes and the crystals which have precipitated are then filtered. The crude product is recrystallized from ethyl acetate to yield 1-(p-tolylsulphonyl)-2-imino-3- propyl-imidazolidine melting at 96.

The starting material is produced as follows:

b. A solution of 190.5 g of p-toluenesulphonyl chloride 250 ml of acetone is added dropwise during 20 minutes with stirring to a solution of 43.0 g of aziridine in 300 ml of 4 N Sodium hydroxide solution which has been cooled to 10. The reaction mixture is stirred for 2 hours at 010 with cooling. 2 liters of water are then added to the mixture and it is extracted three times with 500ml of ether. The ether extract is dried over sodium sulphate and concentrated under vacuum. The residue, crude 1-(p-toly1sulphonyl)-aziridine, melts at 5456.

c. A solution of 19.7 g of l-(p-tolylsulphonyl)- aziridine in 100 ml of dioxane and 15 ml of water is added dropwise at room temperature to 100 ml of propylamine, and the reaction mixture is refluxed for 1 hour. It is then concentrated under vacuum. Recrystallization of the residue from ethyl acetate/petroleum ether yields pure N-(2-propylamine-ethyl)-p-toluenesulphonamide, m.p. 39-41.

EXAMPLE 71 Analogously to Example 70 (a), starting from 10.6 g of cyanogen bromide, the following end products are obtained: 7

a. with 27.0 g of N(2-tert-butylamino-ethyl)-ptoluene-sulphonamide, m.p. 6768 (from ethyl acetate/ether), 1-(p-tolylsu1phony1)-2-imino-3-tertbutyl-imidazolidine, m.p. -131 [the starting product is produced analogously to Example 70 (c) from 19.7 g of l(p-tolylsulphonyl)-aziridine and 100 ml of tert-butylamine] and b. with 29.6 g of N-(2-cyclohexylamino-ethyl)-p toluene-sulphenamide, m.p. 6566 (from ether), 1- (p-tolylsulphonyl)-2-imino-3-cyclohexylimidazolidine, m.p. 1l8-120 [the starting product is produced analogously to Example 70 c) from 19.7 g of l-(tolylsulphonyl)-aziridine and 100 ml of cyclo-hexylamine].

EXAMPLE 72 a. A solution of 11.2 g of cyanogen bromide in 120 ml of ether is added during 10 minutes at room temperature to a solution of 35.0 g of N[2-(1-adamantylamino)-ethyl]-p-toluenesulphonamide in ml of dioxane. The resulting suspension is refluxed for 90 minutes at a bath temperature of 70. The reaction mixture is then concentrated and the oily residue is taken up in 2 N sodium hydroxide solution and methylene chloride. The organic phase is washed with water, dried 

2. A composition according to claim 1, in which compound n is 0; each of R1 and R2 are hydrogen; each of R3 and R4 independently of the other is hydrogen or lower alkyl, R5 is alkyl of from one to five carbon atoms or cycloalkyl having at most 5 carbon atoms; and X is amino, chloro, methoxy or acetyl.
 3. A composition according to claim 1, in which 0; n is 0: R1, R2, R3 and R4 are hydrogen; R5 is n-butyl; and X is amino.
 4. A composition according to claim 1, in which compound n is 0; R1, R2, R3 and R4 are hydrogen; R5 is n-butyl; and X is chloro.
 5. A method of producing a hypoglycemic effect in a mammal, comprising administering to said mammal a hypoglycemically effective amount of a compound as defined in claim
 1. 6. A method of producing a hypoglycemic effect in a mammal, comprising administering to said mammal a hypoglycemically effective amount of a compound as defined in claim
 2. 7. A method of producing a hypoglycemic effect in a mammal, comprising administering to said mammal a hypoglycemically effective amount of a compound as defined in claim
 3. 8. A method of producing a hypoglycemic effect in a mammal, comprising administering to said mammal a hypoglycemically effective amount of a compound as defined in claim
 4. 